Compounds useful in therapy

ABSTRACT

Compounds of formula (I):  
                 
 
     or pharmaceutically acceptable salts or solvates thereof, wherein  
     R 1  represents C 1-4  alkyl;  
     R 2  represents halo, C 1-4  alkyl, C 3-6  cycloalkyl, C 3-6  cycloalkyloxy, —SO 2 (C 1-4  alkyl), optionally substituted C 1-4  alkyloxy, Het or —OHet;  
     R 3  represents a bicyclic group of the formula  
                 
 
      wherein X and Y are selected from C and N, provided that at least one is C;  
     Ring A together with X and Y represents a 5- or 6-membered aromatic ring containing 0, 1, 2 or 3 nitrogen atoms in the ring; n is), 1 or 2  
     L represents a direct link, C 1-4  alkylene or C 1-4  alkoxyalkylene;  
     R 4  represents H, —NR 5 R 6 , C 3-6  cycloalkyl, —OR 7 , Het 1  or Het 4 ;  
     R 5  and R 6  are independently selected from H, C 3-6  cycloalkyl, C 3-6  cycloalkyl-C 1-4  alkylene, —SO 2 (C 1-4  alkyl) and optionally substituted C 1-4  alkyl  
     R 7  is selected from H, C 1-4  alkyl, C 1-4  alkoxyalkyl, C 3-6 cycloalkyl, Het 2  and C 1-4 alkyl-Het 3 ;  
     R 8  is H or C 1-4  alkyl;  
     Het, Het 1 , Het 2  and Het 3  independently represent an optionally substituted 4 to 7 membered saturated heterocyclic group which may be mono- or bi-cyclic and which contains one or more heteroatoms selected from N, O or S;  
     Het 4  represents an optionally substituted 5 or 6 membered unsaturated heterocyclic group containing one or more heteroatoms selected from N, O or S;  
     R 9  is H or C 1-4  alkyl;  
     R 10  and R 11  are independently selected from H and C 1-4  alkyl;  
     are useful in the treatment of hypertension, myocardial infarction, male erectile dysfunction (MED), hyperlipidaemia, cardiac arrhythmia, glaucoma and benign prostatic hyperplasia (BPH). They also find utility in the treatment of female sexual arousal dysfunction (FSAD).

[0001] This invention relates to novel compounds useful in therapy. Italso relates to compositions containing such derivatives and to theiruse. They have potential utility in the treatment of hypertension,myocardial infarction, male erectile dysfunction (MED), hyperlipidaemia,cardiac arrhythmia, glaucoma and benign prostatic hyperplasia (BPH).They also may be useful in the treatment of female sexual arousaldysfunction (FSAD).

[0002] International Patent Application WO 97/23462 discloses quinolineand quinazoline compounds having a 5-phenyl substituent. The compoundsare indicated in the treatment of benign prostatic hyperplasia.

[0003] International Patent application WO 98/30560 discloses quinolineand quinazoline compounds indicated in the treatment of benign prostatichyperplasia.

[0004] International Patent application WO02/053558 (published after thepriority date of this application) discloses quinazoline derivativesindicated in the treatment of benign prostatic hyperplasia.

[0005] According to the present invention, there are provided compoundsof the formula (I):

[0006] and pharmaceutically acceptable salts or solvates thereof,wherein

[0007] R¹ represents C₁₋₄ alkyl;

[0008] R² represents halo, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyloxy, —SO₂(C₁₋₄ alkyl), C₁₋₄ alkyloxy (optionally substitutedby C₃-C₆ cycloalkyl or C₁-C₄ alkoxy), Het or —OHet;

[0009] R³ represents a bicyclic group of the formula

[0010]  wherein X and Y are selected from C and N, provided that atleast one is C;

[0011] Ring A together with X and Y represents a 5- or 6-memberedaromatic ring containing 0, 1, 2 or 3 nitrogen atoms in the ring;

[0012] n is 0, 1 or 2

[0013] L independently represents a direct link, C₁₋₄ alkylene or C₁₋₄alkoxyalkylene;

[0014] R⁴ independently represents H, —NR⁵R⁶, C₃₋₆ cycloalkyl, —OR⁷,Het¹ or Het⁴;

[0015] R⁵ and R⁶ are independently selected from H, C₃₋₆ cycloalkyl,C₃₋₆ cycloalkyl-C₁₋₄ alkylene, —SO₂(C₁₋₄ alkyl) and C₁₋₄ alkyl(optionally substituted with —OR⁸, —NR¹⁰R¹¹, Het¹ or Het⁴);

[0016] R⁷ is selected from H, C₁₋₄ alkyl, C₁₋₄ alkoxyalkyl,C₃₋₆cycloalkyl, Het² and C₁₋₄alkyl-Het³;

[0017] R⁸ is H or C₁₋₄ alkyl;

[0018] Het, Het¹, Het² and Het³ independently represent a 4 to 7membered saturated heterocyclic group which may be mono- or bi-cyclicand which contains one or more heteroatoms selected from N, O or S,optionally substituted with OR⁹ and/or C₁₋₄ alkyl optionally substitutedby OR⁹;

[0019] Het⁴ represents a 5 or 6 membered unsaturated heterocyclic groupcontaining one or more heteroatoms selected from N, O or S, optionallysubstituted with C₁₋₄ alkyl;

[0020] R⁹ is H or C₁₋₄ alkyl;

[0021] R¹⁰ and R¹¹ are independently selected from H and C₁₋₄ alkyl.

[0022] In the above definitions alkyl, alkoxy and cycloalkyl groupscontaining the requisite number of carbon atoms, except where indicated,can be unbranched- or branched-chain. Examples of alkyl groups includemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl andt-butyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

[0023] Unless otherwise provided herein:

[0024] WSCDI means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride;

[0025] DCC means N,N′-dicyclohexylcarbodiimide;

[0026] HOAT means 1-hydroxy-7-azabenzotriazole;

[0027] HOBT means 1-hydroxybenzotriazole hydrate;

[0028] PyBOP® means Benzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexafluorophosphate;

[0029] PyBrOP® means bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate;

[0030] Mukaiyama's reagent means 2-chloro-1-methylpyridinium iodide;

[0031] KHMDS means potassium bis(trimethylsilyl)amide;

[0032] Hünig's base means N-ethyldiisopropylamine;

[0033] Et₃N means triethylamine;

[0034] NMM means N-methylmorpholine;

[0035] DEAD means diethyl azodicarboxylate;

[0036] DIAD means diisopropyl azodicarboxylate;

[0037] DIBAL-H means diisobutylaluminium hydride;

[0038] BINAP means 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl;

[0039] Dba means dibenzylideneacetone;

[0040] Boc means tert-butoxycarbonyl;

[0041] CBz means benzyloxycarbonyl;

[0042] (Boc)₂O means di-tert-butyl dicarbonate;

[0043] MeOH means methanol, EtOH means ethanol, and EtOAc means ethylacetate;

[0044] THF means tetrahydrofuran, DMSO means dimethyl sulphoxide, andDCM means dichloromethane;

[0045] AcOH means acetic acid, TFA means trifluoroacetic acid;

[0046] TFAA means trifluoroacetic anhydride and NMMO means4-methylmorpholine

[0047] N-oxide monohydrate.

[0048] The pharmaceutically acceptable salts of the compounds of theformula (I) include the acid addition and base salts thereof. Suitableacid addition salts are formed from acids which form non-toxic salts andexamples are the hydrochloride, hydrobromide, hydroiodide, sulphate,bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate,fumerate, lactate, tartrate, citrate, gluconate, succinate, saccharate,benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate,p-toluenesulphonate and palmoate salts.

[0049] Suitable base salts are formed from bases which form non-toxicsalts and examples are the sodium, potassium, aluminium, calcium,magnesium, zinc and diethanolamine salts. For a review on suitable saltssee Berge et al, J. Pharm. Sci, 66, 1-19, 1977.

[0050] The pharmaceutically acceptable solvates of the compounds of theformula (I) or salts thereof include the hydrates thereof.

[0051] Also included within the present scope of the compounds of theformula (I) are polymorphs thereof.

[0052] A compound of the formula (I) may contain one or more asymmetriccarbon atoms and therefore exist in two or more stereoisomeric forms.The present invention includes the individual stereoisomers of thecompounds of formula (I) along with the individual tautomeric forms (1a,1b and 1c) thereof, together with mixtures thereof.

[0053] Separation of diastereoisomers may be achieved by conventionaltechniques, e.g. by fractional crystallisation, chromatography orH.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) ora suitable salt or derivative thereof. An individual enantiomer of acompound of the formula (I) may also be prepared from a correspondingoptically pure intermediate or by resolution, such as by H.P.L.C. of thecorresponding racemate using a suitable chiral support or by fractionalcrystallisation of the diastereoisomeric salts formed by reaction of thecorresponding racemate with a suitable optically active acid or base, asappropriate.

[0054] The present invention also includes all suitable isotopicvariations of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof. An isotopic variation of a compound of theformula (I) or a pharmaceutically acceptable salt thereof is defined asone in which at least one atom is replaced by an atom having the sameatomic number but an atomic mass different from the atomic mass usuallyfound in nature. Examples of isotopes that can be incorporated intocompounds of the formula (I) and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulphur, fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O,³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Certain isotopic variationsof the compounds of the formula (I) and pharmaceutically acceptablesalts thereof, for example, those in which a radioactive isotope such as³H or ¹⁴C is incorporated, are useful in drug and/or substrate tissuedistribution studies. Tritiated, i.e. ³H, and carbon-14, i.e. ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with isotopes such as deuterium,i.e. ²H, may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example, increased in vivo half-life orreduced dosage requirements and hence may be preferred in somecircumstances. Isotopic variations of the compounds of formula (I) andpharmaceutically acceptable salts thereof of this invention cangenerally be prepared by conventional procedures such as by theillustrative methods or by the preparations described in the Examplesand Preparations hereafter using appropriate isotopic variations ofsuitable reagents.

[0055] Preferred groups of compounds that may be mentioned include thosein which:

[0056] Het¹, Het² and Het³ contain at least one N atom and are linked toL through an N atom.

[0057] More preferred groups of compounds include those in which:

[0058] Het¹, Het² and Het³ include azetidine, pyrrolidine, piperidine,piperazine, azepane, morpholine, homomorpholine, or one of the followingring systems:

[0059] optionally substituted by OR⁹ and/or C₁₋₄ alkyl optionallysubstituted by OR⁹.

[0060] Still more preferred groups of compounds that may be mentionedinclude those in which:

[0061] (a) R¹ is CH₃;

[0062] (b) R² is cyclopropyl;

[0063] (c) L is methylene;

[0064] (d) R³ represents a group chosen from a or b (bonded to thequinazolinone through the N-atom as indicated)

[0065]  where LR⁴ is CH₂Het¹ or CH₂NR⁵R⁶ and Het¹, R⁵ and R⁶ are ashereinbefore defined;

[0066] (e) Het¹ represents an N-linked morpholinyl

[0067] (f) R⁵ and R⁶ are independently selected from H or C₁₋₃ alkyloptionally substituted by OCH₃;

[0068] (g) Het¹, Het² and Het³ are selected from the group comprisingpyrrolidine, piperidine, morpholine or

[0069] Compounds that may be prepared according to the invention,amongst others, are:

[0070]5-cyclopropyl-7-methoxy-2-(2-(4-methoxypiperidin-1-ylmethyl)-7,8-dihydro[1,6]naphthyridin-6(5H)-yl)-4(3H)-quinazolinone;

[0071]5-cyclopropyl-7-methoxy-2-(2-([dimethylamino]methyl)-7,8-dihydro[1,6]naphthyridin-6(5H)-yl)-4(3H)-quinazolinone;

[0072]5-cyclopropyl-7-methoxy-2-(2-(1-pyrrolidinylmethyl)-7,8-dihydro[1,6]naphthyridin-6(5H)-yl)-4(3H)-quinazolinone;

[0073]5-cyclopropyl-7-methoxy-2-(2-(4-morpholinylmethyl)-7,8-dihydro[1,6]naphthyridin-6(5H)-yl)-4(3H)-quinazolinone;

[0074]5-cyclopropyl-7-methoxy-2-(5-([dimethylamino]methyl)-3,4-dihydro[2,6]naphthyridin-2(1H)-yl)-4(3H)-quinazolinone;

[0075]5-cyclopropyl-7-methoxy-2-(5-(1-pyrrolidinylmethyl)-3,4-dihydro[2,6]naphthyridin-2(1H)-yl)-4(3H)-quinazolinone;

[0076]5-cyclopropyl-7-methoxy-2-(5-(1-piperidinylmethyl)-3,4-dihydro[2,6]naphthyridin-2(1H)-yl)-4(3H)-quinazolinone;

[0077]5-cyclopropyl-7-methoxy-2-(5-(4-morpholinylmethyl)-3,4-dihydro[2,6]naphthyridin-2(1H)-yl)-4(3H)-quinazolinone;

[0078]5-cyclopropyl-7-methoxy-2-(5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-3,4-dihydro[2,6]naphthyridin-2(1H)-yl)-4(3H)-quinazolinone;

[0079]5-cyclopropyl-7-methoxy-2-(2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-7,8-dihydro[1,6]naphthyridin-6(5H)-yl)-4(3H)-quinazolinone;

[0080]5-cyclopropyl-7-methoxy-2-[3-(morpholin-4-ylmethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl]-4(3H)-4(3H)-quinazolinone;

[0081]5-cyclopropyl-2-[3-(hydroxymethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl]-7-methoxy-4(3H)-quinazolinone;

[0082]5-cyclopropyl-7-methoxy-2-[3-(4-methoxypiperidin-1-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl]-4(3H)-quinazolinone;

[0083]5-cyclobutyl-7-methoxy-2-[2-(morpholin-4-ylmethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinone;

[0084]2-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-isopropyl-7-methoxy-4(3H)-quinazolinone;

[0085]5-isopropyl-7-methoxy-2-[5-(morpholin-4-ylmethyl)-3,4-dihydroiso-4(3H)-quinolin-2(1H)-yl]-4(3H)-quinazolinone;

[0086]5-isopropyl-7-methoxy-2-[2-[(pyridin-2-ylmethyl)amino]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinone;

[0087]N-{2-[5-(cyclobutyloxy)-7-methoxy-4-oxo-3,4-dihydro-2-quinazolinyl]-1,2,3,4-tetrahydro-5-iso-4(3H)-quinolinyl}methanesulfonamide;

[0088]2-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-isopropoxy-7-methoxy-4(3H)-quinazolinone;

[0089]5-isopropoxy-7-methoxy-2-[2-[(2-methoxyethyl)amino]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinone;

[0090]5-(cyclobutyloxy)-2-[5-[(diethylamino)methyl]-3,4-dihydroiso-4(3H)-quinolin-2(1H)-yl]-7-methoxy-4(3H)-quinazolinone;

[0091]2-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-7-methoxy-5-(tetrahydrofuran-3-yloxy)-4(3H)-quinazolinone;

[0092]7-methoxy-2-[2-[(2-methoxyethyl)amino]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-5-(tetrahydrofuran-3-yloxy)-4(3H)-quinazolinone;

[0093]7-methoxy-2-[2-[(pyridin-2-ylmethyl)amino]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-5-(tetrahydrofuran-3-yloxy)-4(3H)-quinazolinone;

[0094]2-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-7-methoxy-5-(2-methoxyethoxy)-4(3H)-quinazolinone;

[0095]7-methoxy-5-(2-methoxyethoxy)-2-[5-[(pyridin-2-ylmethyl)amino]-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-4(3H)-quinazolinone;

[0096]7-methoxy-5-(2-methoxyethoxy)-2-[2-[(2-methoxyethyl)amino]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinone;

[0097]7-methoxy-5-(2-methoxyethoxy)-2-[2-[(pyridin-2-ylmethyl)amino]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinone;

[0098]5-(cyclopropylmethoxy)-2-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-7-methoxy-4(3H)-quinazolinone;

[0099]5-(cyclopropylmethoxy)-7-methoxy-2-[5-[(pyridin-2-ylmethyl)amino]-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-4(3H)-quinazolinone;

[0100]5-(cyclopropylmethoxy)-7-methoxy-2-[2-[(pyridin-2-ylmethyl)amino]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinone;

[0101]5-isopropoxy-7-methoxy-2-[2-[(pyridin-2-ylmethyl)amino]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinone;

[0102]5-cyclopropyl-7-methoxy-2-[5-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-3,4-dihydroiso-4(3H)-quinolin-2(1H)-yl]-4(3H)-quinazolinone;

[0103]5-cyclopropyl-7-methoxy-2-[5-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-3,4-dihydroiso-4(3H)-quinolin-2(1H)-yl]-4(3H)-quinazolinone;

[0104]5-cyclopropyl-7-methoxy-2-[5-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-3,4-dihydroiso-4(3H)-quinolin-2(1H)-yl]-4(3H)-quinazolinone;

[0105]5-cyclopropyl-7-methoxy-2-[5-{[(2R)-1-methylpyrrolidin-2-yl]methoxy}-3,4-dihydroiso-4(3H)-quinolin-2(1H)-yl]-4(3H)-quinazolinone;

[0106]5-cyclopropyl-7-methoxy-2-(2-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-4(3H)-quinazolinone;

[0107]5-cyclopropyl-7-methoxy-2-[2-(1-methylpiperidin-4-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinone;

[0108]5-cyclopropyl-2-[2-{[(2-hydroxyethyl)amino]methyl}-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-7-methoxy-4(3H)-quinazolinone;

[0109]5-cyclopropyl-7-methoxy-2-[2-{[(2-methoxyethyl)(methyl)amino]methyl}-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinone;

[0110]5-cyclopropyl-7-methoxy-2-[5-[(3-methoxyazetidin-1-yl)methyl]-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-4(3H)-quinazolinone;

[0111]5-cyclopropyl-7-methoxy-2-[5-{[(3S)-3-methoxypyrrolidin-1-yl]methyl}-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-4(3H)-quinazolinone;

[0112]5-cyclopropyl-7-methoxy-2-[5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-4(3H)-quinazolinone;

[0113]5-cyclopropyl-7-methoxy-2-[2-{[[(1S)-2-methoxy-1-methylethyl](methyl)amino]methyl}-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-4(3H)-quinazolinone;

[0114]5-cyclopropyl-7-methoxy-2-[2-[(4-methoxypiperidin-1-yl)methyl]-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-4(3H)-quinazolinone;

[0115]5-cyclopropyl-2-[3-(cyclopropylmethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl]-7-methoxy-4(3H)-quinazolinone;

[0116]5-cyclopropyl-7-methoxy-2-(3-morpholin-4-yl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-4(3H)-quinazolinone;

[0117]5-cyclopropyl-7-methoxy-2-[2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinone;

[0118]5-cyclohexyl-7-methoxy-2-[2-(morpholin-4-ylmethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinone;

[0119]5-isopropyl-7-methoxy-2-[2-[(2-methoxyethyl)amino]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinone;

[0120]5-isopropyl-7-methoxy-2-[5-(morpholin-4-ylmethyl)-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-4(3H)-quinazolinonedihydrochloride;

[0121]5-isopropyl-7-methoxy-2-[5-{[(2-methoxyethyl)(methyl)amino]methyl}-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-4(3H)-quinazolinonedihydrochloride;

[0122]5-isopropyl-7-methoxy-2-[2-(pyrrolidin-1-ylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-4(3H)-quinazolinonedihydrochloride;

[0123]2-(5-amino-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)-5-isopropyl-7-methoxy-4(3H)-quinazolinonedihydrochloride;

[0124]2-[4-amino-2-[(2-methoxyethyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-5-isopropyl-7-methoxy-4(3H)-quinazolinonedihydrochloride;

[0125]5-isopropyl-7-methoxy-2-[2-(methylamino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinonedihydrochloride;

[0126]2-[4-[ethyl(methyl)amino]-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl]-5-isopropyl-7-methoxy-4(3H)-quinazolinonedihydrochloride;

[0127]⁵-isopropyl-7-methoxy-2-[5-[(3-methoxyazetidin-1-yl)methyl]-3,4-dihydroiso-4(3H)-quinolin-2(1H)-yl]-4(3H)-quinazolinonedihydrochloride;

[0128]5-isopropyl-7-methoxy-2-[5-[(pyridin-2-ylmethyl)amino]-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-4(3H)-quinazolinonedihydrochloride;

[0129]⁵-isopropyl-7-methoxy-2-[5-{[(2-methoxyethyl)amino]methyl}-3,4-dihydroiso-4(3H)-quinolin-2(1H)-yl]-4(3H)-quinazolinonedihydrochloride;

[0130]2-[5-{[2-(dimethylamino)ethyl]amino}-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-5-isopropyl-7-methoxy-4(3H)-quinazolinonetrihydrochloride;

[0131]2-[5-[(dimethylamino)methyl]-3,4-dihydroiso-4(3H)-quinolin-2(1H)-yl]-5-isopropyl-7-methoxy-4(3H)-quinazolinonedihydrochloride;

[0132]2-[4-amino-2-(dimethylamino)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl]-5-isopropyl-7-methoxy-4(3H)-quinazolinonedihydrochloride;

[0133]2-[2-(dimethylamino)-4-[(2-methoxyethyl)amino]-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl]-5-isopropyl-7-methoxy-4(3H)-quinazolinonetrihydrochloride;

[0134]5-isopropyl-7-methoxy-2-[5-[(4-methoxypiperidin-1-yl)methyl]-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-4(3H)-quinazolinonedihydrochloride;

[0135]5isopropyl-7-methoxy-2-[5-[(3-methoxyazetidin-1-yl)methyl]-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-4(3H)-quinazolinonedihydrochloride;

[0136]5-isopropyl-7-methoxy-2-[2-(morpholin-4-ylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-4(3H)-quinazolinonedihydrochloride;

[0137]2-[5-[(dimethylamino)methyl]-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-5-isopropyl-7-methoxy-4(3H)-quinazolinonedihydrochloride;

[0138]2-[2-{[2-(dimethylamino)ethyl]amino}-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-5-isopropyl-7-methoxy-4(3H)-quinazolinonetrihydrochloride;

[0139]5-isopropyl-7-methoxy-2-[5-[(2-methyl-1H-imidazol-1-yl)methyl]-3,4-dihydroiso-4(3H)-quinolin-2(1H)-yl]-4(3H)-quinazolinonedihydrochloride;

[0140]7-methoxy-2-[2-{[(2-methoxyethyl)(methyl)amino]methyl}-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-5-tetrahydro-2H-pyran-4-yl-4(3H)-quinazolinonedihydrochloride;

[0141]7-methoxy-2-[2-(pyrrolidin-1-ylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-5-tetrahydro-2H-pyran-4-yl-4(3H)-quinazolinonedihydrochloride;

[0142]2-(2-[(dimethylamino)methyl]-7,8-dihydropyrido[4,3d]pyrimidin-6(5H)-yl)-7-methoxy-5-tetrahydro-2H-pyran-4-yl-4(3H)-quinazolinonedihydrochloride;

[0143]7-methoxy-2-[5-(pyrrolidin-1-ylmethyl)-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-5-tetrahydro-2H-pyran-4-yl-4(3H)-quinazolinonedihydrochloride;

[0144]2-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-7-methoxy-5-tetrahydro-2H-pyran-4-yl-4(3H)-quinazolinonehydrochloride;

[0145]7-methoxy-2-[5-(morpholin-4-ylmethyl)-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-5-tetrahydro-2H-pyran-4-yl-4(3H)-quinazolinonedihydrochloride;

[0146]2-[5-[(dimethylamino)methyl]-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-7-methoxy-5-tetrahydro-2H-pyran-4-yl-4(3H)-quinazolinonedihydrochloride;

[0147]7-methoxy-2-[5-(morpholin-4-ylmethyl)-3,4-dihydroiso-4(3H)-quinolin-2(1H)-yl]-5-tetrahydro-2H-pyran-4-yl-4(3H)-quinazolinonedihydrochloride;

[0148]7-methoxy-2-[5-[(3-methoxyazetidin-1-yl)methyl]-3,4-dihydroiso-4(3H)-quinolin-2(1H)-yl]-5-tetrahydro-2H-pyran-4-yl-4(3H)-quinazolinonedihydrochloride;

[0149]7-methoxy-2-[2-[(2-pyrrolidin-1-ylethyl)amino]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-5-tetrahydrofuran-2-yl-4(3H)-quinazolinonetrihydrochloride;

[0150]7-methoxy-2-[2-[(2-methoxyethyl)amino]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-5-tetrahydrofuran-2-yl-4(3H)-quinazolinonedihydrochloride;

[0151]2-[2-{[2-(dimethylamino)ethyl]amino}-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-7-methoxy-5-tetrahydrofuran-2-yl-4(3H)-quinazolinonetrihydrochloride;

[0152]2-(5-amino-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)-7-methoxy-5-tetrahydrofuran-2-yl-4(3H)-quinazolinonetrihydrochloride;

[0153]5-chloro-7-methoxy-2-[2-(pyrrolidin-1-ylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-4(3H)-quinazolinonedihydrochloride;

[0154]5-chloro-7-methoxy-2-(5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethy]-3,4-dihydro[2,6]naphthyridin-2(1H)-yl)-4(3H)-quinazolinonedihydrochloride;

[0155]5-cyclopropyl-2-[2-{[ethyl(2-methoxyethyl)amino]methyl}-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-7-methoxy-4(3H)-quinazolinonedihydrochloride;

[0156]2-[2-(aminomethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-5-isopropyl-7-methoxy-4(3H)-quinazolinonedihydrochloride;

[0157]2-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-7-methoxy-5-(1-methylpiperidin-2-yl)-4(3H)-quinazolinonetrihydrochloride;

[0158] 2-(6,7-dimethoxy-3,4-dihydroiso-4(3H)-quinolin-2(1H)-yl)-7-methoxy-5-(1-methylpiperidin-2-yl)-4(3H)-quinazolinonedihydrochloride;

[0159]7-methoxy-2-[2-[(2-methoxyethyl)amino]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-5-(1-methylpiperidin-2-yl)-4(3H)-quinazolinonetrihydrochloride;

[0160]5-(butylsulfonyl)-7-methoxy-2-[5-[(2-methoxyethyl)amino]-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-4(3H)-quinazolinone;

[0161]5-(butylsulfonyl)-7-methoxy-2-[5-[(pyridin-2-ylmethyl)amino]-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-4(3H)-quinazolinone;

[0162]5-isopropyl-7-methoxy-2-[1-(2-pyrrolidin-1-ylethyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-4(3H)-quinazolinone;

[0163]5-isopropyl-7-methoxy-2-[2-(2-pyrrolidin-1-ylethyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-4(3H)-quinazolinone;

[0164]5-chloro-7-methoxy-2-[5-(pyrrolidin-1-ylmethyl)-3,4-dihydro-2,6-naphthyridin-2(1H)-yl]-4(3H)-quinazolinone;

[0165]5-isopropyl-7-methoxy-2-[2-(4-methylpiperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-4(3H)-quinazolinonetrihydrochloride;

[0166]5-Isopropyl-7-methoxy-2-(5-methylaminomethyl-3,4-dihydro-1H-[2,6]naphthyridin-2-yl)-3H-quinazolin-4-onedihydrochloride;

[0167] and pharmaceutically acceptable salts or solvates thereof.

[0168] The compounds of the invention are useful because they possesspharmacological activity in animals. In particular, the compounds areuseful in the treatment of a number of conditions includinghypertension, myocardial infarction, male erectile dysfunction,hyperlipidaemia, cardiac arrhythmia, glaucoma and benign prostatichyperplasia. They may also be useful in the treatment of female sexualarousal dysfunction. Benign prostatic hyperplasia is of greatestinterest.

[0169] Thus, according to another aspect of the invention, there isprovided a pharmaceutical composition including a compound of theformula (I), a tautomer, or a pharmaceutically acceptable salt orsolvate thereof, together with a pharmaceutically acceptable excipient,diluent or carrier. Also provided is a method of treatment of benignprostatic hyperplasia, which comprises administering a therapeuticallyeffective amount of a compound of the invention to a patient sufferingfrom such a disorder. The use of the compounds of the invention aspharmaceuticals, and the use of the compounds of the invention in themanufacture of a medicament for the treatment of benign prostatichyperplasia, are also provided.

[0170] The compounds of the invention may be administered by anyconvenient route, for example orally, parenterally (e.g. intravenously,transdermally) or rectally. The daily dose required will of course varywith the particular compound used, the particular condition beingtreated and with the severity of that condition. However, in general atotal daily dose of from about 0.01 to 10.0 mg/kg of body weight, andpreferably about 0.01 to 2.5 mg/kg, is suitable, administered from 1 to2 times a day. Oral administration is of particular interest.

[0171] The compounds of the invention will generally be administered inthe form of a suitable pharmaceutical formulation. Thus, according toanother aspect of the invention, there is provided a pharmaceuticalformulation including preferably less than 50% by weight of a compoundof the invention in admixture with a pharmaceutically acceptableadjuvant, diluent or carrier. The pharmaceutical formulation ispreferably in unit dose form. Such forms include solid dosage forms, forexample tablets, pills, capsules, powders, granules, and suppositoriesfor oral, parenteral or rectal administration; and liquid dosage forms,for example sterile parenteral solutions or suspensions, suitablyflavoured syrups, flavoured emulsions with edible oils such ascottonseed oil, sesame oil, coconut oil and peanut oil, and elixirs andsimilar pharmaceutical vehicles. Oral formulations are preferablycontrolled-release formulations.

[0172] Solid formulations may be prepared by mixing the activeingredient with pharmaceutical carriers, for example conventionaltabletting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate, gums andother diluents, for example water, to form a homogeneous preformulationformulation in which the active ingredient is uniformly dispersed sothat it may be readily subdivided into equally effective unit dosageforms containing typically from 1.0 to about 70.0 mg of the activeingredient. The solid dosage forms may be coated or otherwise compoundedto prolong the action of the formulation.

[0173] Formulations intended for the treatment of benign prostatichyperplasia may contain a compound of the invention in combination witha compound that attenuates the growth of the prostate gland. Forexample, a formulation is envisaged that combines a compound of theinvention with human 5-α reductase inhibitory compound [seeInternational Patent Application WO 95/28397]. Alternatively, a compoundof the invention could be presented in a pharmaceutical pack alsocontaining a human 5-α reductase inhibitory compound as a combinedpreparation for simultaneous, separate or sequential use.

[0174] The compounds of the invention may be tested in the screen setout below:

[0175] Contractile Responses of Rabbit Aorta (α_(1L) Receptor)

[0176] A single rabbit aorta was cleaned of connective tissue, cut intorings ˜3 mm in length, then denuded of epithelium by rubbing very gentlywith a probe. The lengths of tissue are then mounted in the 5 mL organbaths, which contain the modified Krebs of the following composition(mM): NaCl (119), KCl (4.7), CaCl₂ (2.5), KH₂PO₄ (1.2), MgSO₄ (1.2),NaHCO₃ (25), glucose (11), and gassed with 95% O₂/5% CO₂. The tissuesare placed under ˜1.5 g tension, and are left to equilibrate for ˜60minutes on a pump speed of ˜5 mL\minute, adjusting the tension to 1-1.5g if necessary after 15 and 45 minutes. A 1M stock solution (1×10⁻³Mbath conc.) of methoxamine in water was made and 1:10 dilutions madeusing the same diluent. A sensitising dose of 120 mM KCl (bathconcentration) was added to each bath. After the maximum response hadbeen reached (usually about 6-8 minutes), the tissues are washed withKrebs solution for 60 minutes, pump speed at ˜2.97 mL/min.

[0177] A cumulative dose response curve was constructed, bathconcentrations of methoxamine being 1×10⁻⁷M to a maximum of 3×10⁻⁴M.Each dose was allowed to exert its maximum effect before the next dosewas added (6-8 mins). On completion of this curve, the tissues werewashed, (pump speed ˜10 mL/min for 10 minutes, 2.97 mL/min for 50minutes) until the tissues were stable at baseline tension.

[0178] The compound under investigation was made up to a stockconcentration of 1 mM in 100% DMSO. Three chosen concentrations for apA₂ estimation were then made up in DMSO, and 5 μl of each concentrationadded in duplicate to the tissues, with a vehicle control (DMSO). Thetissues were left in the presence of compound or vehicle for 60 minutesbefore a second CDRC to methoxamine was constructed up to a maximum of3×10⁻³M

[0179] The data was captured on ADA analysis in-vitro software, whichexpresses the readings as a % of the maximum response of the controlcurve, draws control and test compound dose response curves, andcalculates a EC₅₀ and then dose ratio (DR), the ratio between controland treatment curve EC₅₀, for each treatment. The results are reportedas pK_(b), or where possible pA₂. $\begin{matrix}{{pKb} = {{- \log}\frac{\left\lbrack {{Antagonist}\quad {concentration}} \right\rbrack}{\left( {{DR}^{*} - 1} \right)}}} \\{{{where}\quad {DR}^{*}} = \frac{{dose}\quad {ratio}\quad {compound}}{{dose}\quad {ratio}\quad {control}}}\end{matrix}$

[0180] NB. If the value of (DR*−1) was less than or equal to 2, theresult could not be used for a pA₂ estimation. The control curves mustnot have shifted by more than 2.5. The pA₂ was plotted on a Schildanalysis. i.e. y axis=log (DR*−1); x axis=−log antagonist concentration

[0181] The compounds of the invention may have the advantage that theyare more potent, have a longer duration of action, have a broader rangeof activity, are more stable, have fewer side effects or are moreselective (in particular they may have beneficial effects in benignprostatic hyperplasia without causing undesirable cardiovasculareffects, for example because they are able to selectively antagoniseprostatic receptor subtypes of the α₁-adrenoceptor), or have other moreuseful properties than the compounds of the prior art. It will beapparent to those skilled in the art that sensitive functional groupsmay need to be protected and deprotected during synthesis of a compoundof the invention. This may be achieved by conventional techniques, forexample as described in ‘Protective Groups in Organic Synthesis’ by T WGreene and P G M Wuts, John Wiley and Sons Inc, 1991.

[0182] The compounds of the invention may be obtained by the reaction ofan amine (III) with alkylating agent (II) as shown in the scheme below,where R¹, R², X, Y etc. are as previously defined:

[0183] Step (a): Amine (III) is reacted with quinazolinone (II), whereLG is a suitable leaving group (for example halo, tosylate or mesylate),in the presence of an excess of 3° amine base (as H⁺ acceptor) (forexample Et₃N, Hünig's base or NMM) in a suitable high boiling solvent atelevated temperature for 1-6 hrs. For example, preferred conditions fora) are 1-2 eq. amine (III), 1.5-8 eq. of 3° amine base (for example Et₃Nor Hünig's base), in n-BuOH at reflux for 1-6 hours. Preferably leavinggroup LG is Halo. More preferably LG is Cl.

[0184] Quinazolinone (II) may be prepared according to scheme 2, whereR¹ and R² are as previously defined:

[0185] Step (b): This acid/amine coupling may be undertaken by usingeither

[0186] (i) an acyl chloride derivative of acid (IV)+amine, with anexcess of acid acceptor in a suitable solvent, or

[0187] (ii) the acid (IV) with a conventional coupling agent+amine,optionally in the presence of a catalyst, with an excess of acidacceptor in a suitable solvent.

[0188] Typically the conditions are as follows:

[0189] acid chloride of acid (IV) (generated in-situ), an excess ofamine, optionally with an excess of 3° amine such as Et₃N, Hünig's baseor NMM, in DCM or THF, without heating for 1 to 24 hrs, or

[0190] (ii) acid (IV), WSCDI/DCC and HOBT/HOAT, an excess of amine, withan excess of NMM, Et₃N, Hünig's base in THF, DCM or EtOAc, at rt. for 4to 48 hrs; or, acid (IV), PYBOP®/PyBrOP®/Mukaiyama's reagent, an excessof amine, with an excess of NMM, Et₃N, Hünig's base in THF, DCM orEtOAc, at rt. for 4 to 24 hrs.

[0191] The preferred conditions are: acid chloride of acid (IV)(generated in-situ), 3.6 eq. amine, in DCM at r.t. for 1 hr.

[0192] Step (c): The hydroxy group of compound (V) is converted into asuitable leaving group (LG, where LG is halo, mesylate, or tosylate),followed by an in-situ alkylation/ring formation.

[0193] Typically LG is halo. It is preferred that LG is Cl. Chlorinationis carried out under standard conditions, using a chlorinating agent(SOCl₂, POCl₃) optionally in the presence of a 3° amine base (e.g.Hünig's base, Et₃N), optionally in a suitable solvent (DCM) at roomtemperature to reflux temperature for 1-16 hours. Preferred conditionsare: 1.1 eq. SOCl₂, in DCM for 1.5 hrs at rt.

[0194] Step (d): An organometallic addition/elimination is undertaken byreacting fluoro compound (VI) with “activated” R² (such as R²MgBr,R²MgCl, R²Li), in a suitable solvent (tetrahydrofuran, ether,cyclohexane, 1,4-dioxane) at 0° C. to room temperature for 1-24 hrs.Preferred conditions are: 1-2 eq. of R²MgBr or R²MgCl (generatedin-situ, using standard Grignard methodology), 1 eq. of fluoro compound(VI), in tetrahydrofuran, at between 0° C. and room temperature, for 3hours.

[0195] Step (e): The nitrile (VIII) is preferably formed from compound(VII) under the following conditions: 2 eq. POCl₃, 10 eq. pyridine,EtOAc, reflux for 5 hours.

[0196] Step (f): Amination of compound (VIII) is achieved by reactionwith R^(a)NH₂ (R^(a) is H) at an elevated temperature and pressure, in asuitable solvent (DMSO, MeOH) for about 18-72 hrs. It is preferred tocarry out the reaction under the following conditions: R^(a)NH₂ in DMSOat elevated temperature (about 140° C.) and pressure (sealed vessel) for18-72 hrs.

[0197] Step (g): Quinazolinedione (X) is formed by CO₂ insertion,derived from the method of Mizuno et. al. Tet. Lett. 41 (2000) 1051. Thefollowing conditions are preferred: 2 eq. of DBU(1,8-diazabicyclo[5.4.0]undec-7-ene), CO₂ (solid), inN,N-dimethylformamide, at 140° C. and elevated pressure (sealed vessel)for 18 hrs.

[0198] Step (h): This chlorination step can be done under standardconditions, using an excess of chlorinating agent (SOCl₂, POCl₃)optionally in the presence of a 3° amine base (e.g. Hünig's base, Et₃N),optionally in a suitable solvent (DCM) at room temperature to refluxtemperature for 1-16 hours. It is preferred to use the followingconditions: 30 eq. POCl₃ (as solvent), optionally in the presence of abase, e.g. 2.4 eq. Hünig's base, at reflux for 1-7 hours

[0199] Step (i): Selective hydrolysis of compound (XI) is achieved byreaction with an OH⁻ source (typically an alkali metal hydroxide) in asuitable solvent, at room temperature for 2 hours. Preferred conditionsare: 3 eq. NaOH(aq.) in dioxane at room temperature for 2 hours.

[0200] Suitable amines for use as compound (III) may be prepared asdescribed below in schemes 3 to 13:

[0201] Compounds XVII and XIV can then be further elaborated accordingto schemes 4 and 5 respectively:

[0202] when R⁴ represents NR⁵R⁶ or an N-linked Het,

[0203] When R⁴ represents NR⁵R⁶ or N-linked Het, compounds of formula(XIX) may also be prepared according to scheme 6:

[0204] Step (j): The amine (XIII) is protected using standardmethodology for introducing nitrogen protecting groups, such as thatfound in textbooks, (e.g. “Protecting Groups in Organic Synthesis” by T.W. Greene and P. Wutz). It is preferred to use the tert-butoxycarbonyl(Boc) protecting group which is introduced under the followingconditions: 2.3 eq. (Boc)₂O, in dioxane/1N NaOH solution (1:2 by volume)at room temperature for 16 hrs.

[0205] Step (k): Triflate (XV) is formed by reaction of alcohol (XIV)with a slight excess of a suitable triflating reagent, in the presenceof an excess of a 3° amine base (e.g. Et₃N, NMM, Hünig's base) in asuitable solvent (DCM) at between −30° C. and room temperature for up to24 hours. Preferred conditions are as follows: 1.1 eq.N-phenylbis(trifluoromethanesulphonimide) or triflic anhydride, 1.1 eq.Et₃N, in DCM at 0° C. and room temperature for 2 to 16 hours.

[0206] Step (l): Nitrile (XVI) is obtained via metal catalysed(preferably palladium, nickel) cross-coupling with a suitable nitrilesource (e.g. Zn(CN)₂), in the presence of a suitable additive(preferably LiCl) in a suitable solvent at elevated temperature for upto 24 hrs. It is preferred to use the following conditions: 1 eq.Zn(CN)₂, 1 eq. LiCl, cat Pd(PPh₃)₄, in N,N-dimethylformamide at 110-125°C. for 8 to 24 hrs.

[0207] Step (m): Nitrile (XVI) is reduced with a suitable metal hydridereducing agent (LiAlH₄, NaAlH₄, DIBAL-H) in a suitable solvent (toluene,tetrahydrofuran) at low temp (−78° C.), followed by acid or basecatalysed hydrolysis of the intermediate imine compound to give aldehyde(XVII). Preferred conditions are: 2 eq. DIBAL-H, in toluene at −78° C.for 2 hrs, then MeOH, HCl at −78° C. to 0° C.

[0208] Step (n): Aldehyde (XVII) is reacted with an amine (NR⁵R⁶ orN-linked Het) to form an intermediate compound, which is reduced by asuitable reducing agent, such as NaCN(BH)₃ or Na(OAc)₃BH, optionally inthe presence of NaOAc or AcOH, optionally in the presence of a dryingagent (molecular sieves, MgSO₄) in a suitable solvent (tetrahydrofuran,DCM) at room temperature for 3-72 hrs. Preferred conditions are: 1-2 eq.amine, 2-5 eq. of Na(OAc)₃BH, optionally with 1-4 eq. of AcOH or NaOAc,optionally in the presence of 3 Å sieves, in tetrahydrofuran at roomtemperature for 3-72 hrs.

[0209] Step (o): Deprotection is undertaken using standard methodology,as described in “Protecting Groups in Organic Synthesis” by T. W. Greeneand P. Wutz”.

[0210] When PG is Boc, then preferred conditions are: HCl(g) in DCM orMeOH at rt. for 30 min to 2 hrs, or DCM:TFA (1:1 by volume) at roomtemperature for 3 hrs.

[0211] When PG is benzyl, then the preferred conditions are: 10% Pd/C(1:1 w/w), 2-25 eq. ammonium formate or formic acid, in MeOH at refluxfor between 3 mins and 1.5 hrs, or 10% Pd/C (about 10% w/w), inmethanol, optionally in the presence of HCl, at about 30° C. and 30 psifor about 17 hrs.

[0212] Step (p): A Mitsunobu reaction between alcohol (XIV) andHO(CH₂)₂Het is carried out using standard methodology, as discussed inSynthesis 1 (1981) or Org. React. 42; 335 (1992). Preferred conditionsare: 2.1 eq. DEAD (Diethylazodicarboxylate), 2.25 eq. PPh₃, 2.65 eq. ofHO(CH₂)₂Het, in DCM for 34 hrs at rt.

[0213] Step q: The alcohol (XXII) (when Prot is Boc, the alcohol may beobtained as described in WO 02/053558) may be chlorinated to provide thechloride (XXIII) using standard methodology, but preferably undernon-acidic conditions. Preferred conditions are: 1.2 eq. MeSO₂Cl, and1.5 eq. Et₃N, in tetrahydrofuran for 30 mins, followed by 1.5 eq.Bu₄NCl, at r.t. for about 2 hours.

[0214] Step (r): The chloride (XXIII) is reacted with an amine (R⁵R⁶NH)or N-linked Het, in the presence of a suitable base (e.g. alkali metalhydride, such as NaH or LiH) in a suitable solvent (e.g. ether,tetrahydrofuran) at between room temperature and reflux for up to 18hours to provide compounds of formula (XVIII). Preferred conditions are:1.05 eq. NaH, 1.1 eq. amine/N-linked Het, in tetrahydrofuran at betweenr.t. and reflux for 18 hrs.

[0215] Step (s): Compound (XXIV) is reacted with pyrrolidine, with theconcomitant removal of water, in a suitable high boiling solvent, at anelevated temperature for up to 48 hours, to give compound (XXV). Thefollowing conditions are preferred: 1.5 eq. pyrrolidine and ketone(XXII) in toluene at reflux under Dean and Stark conditions, for 4.5hrs.

[0216] Step (t): 2 equivalents of propiolamide to 1 equivalent ofcompound (XXV) in a high boiling solvent (e.g. Toluene) at reflux for 16hours.

[0217] Step (u): Compound (XXVI) is brominated using standardmethodology, with a suitable brominating agent (POBr₃), optionally inthe presence of anisole, in a suitable solvent (MeCN), at elevated tempfor about 1 hr. The following conditions are preferred: 5 eq. of POBr₃,in MeCN/anisole (1:1 by volume) at 120° C. for 1 hr.

[0218] Step (v): Metalation of compound (XXVII) is undertaken with asuitable base (nBuLi) at low temp (−78° C.), followed by quench of theintermediate anion by an excess of carbonyl or formyl source(N,N-dimethylformamide) for about 1 hr, to give the desired compound.Preferred conditions are: 1.1-1.5 eq. n-BuLi, tetrahydrofuran, −78° C.,for 5-15 min, then 3 eq N,N-dimethylformamide or R⁴COH for 1 hour.

[0219] Compound (XXVIII), when R⁴ in scheme 7 represents H, can then befurther elaborated by reductive amination followed by deprotection in amanner similar to that depicted in scheme 4.

[0220] Compounds (XXIX) and (XXVII) can be further elaborated accordingto schemes 8, 9, 10, and 11 respectively. PG represents a N-protectinggroup, preferably Bn:

[0221] When Het is linked through N,

[0222] Compound (XXVI) may be further reacted to provide compounds whereHet is linked through C, according to scheme 12:

[0223] Step (w): Amination of compound (XXIX) (when PG is Bn, obtainedas described in WO 9830560) is achieved by reaction with R⁵R⁶NH atelevated temperature and pressure, optionally in a suitable solvent(DMSO, MeOH) and optionally in the presence of a suitable catalyst, forabout 18-72 hrs. It is preferred to carry out the reaction under thefollowing conditions: R⁵R⁶NH optionally in DMSO at the refluxtemperature of the reaction, at elevated pressure (sealed vessel) for18-72 hrs, optionally in the presence of CuSO₄.

[0224] Step (x): Reduction of the nitrile (XXXII) to provide the amine(XXXIII) may be achieved using a suitable reducing agent (LiALH₄,BH₃Me₂S) or by hydrogenation in the presence of a suitable metal (e.g.Raney® Nickel). Typically the reaction is carried out according to themethod of Satoh and Suzuki (Tet. Lett. 4555; 1969). The preferredconditions are: 2 eq. CoCl₂, 10 eq. NaBH₄ in MeOH at r.t. for up to 2hrs.

[0225] Step (y): A metal (e.g. palladium, nickel or zinc) catalysedcross-coupling reaction is undertaken, optionally using a suitable base(Nat-BuO, K₂CO₃ or Et₃N), a catalytic amount of suitable additive andmetal catalyst in a suitable solvent such as toluene, dioxan orN,N-dimethylformamide at elevated temp for up to 18 hrs, to give thedesired compound. The preferred conditions are: 3 eq. vinyl ester, 0.1eq. Pd(dba)₃, 0.3 eq. P(t-Bu)₃, excess Et₃N in dioxan at reflux for 17hrs.

[0226] Step (yy): A metal (e.g. palladium, nickel or zinc) catalysedcross-coupling reaction is undertaken, optionally using a suitable base(Nat-BuO, K₂CO₃ or Et₃N), a catalytic amount of suitable additive andmetal catalyst in a suitable solvent such as toluene, dioxan orN,N-dimethylformamide at elevated temp for up to 18 hrs, to give thedesired compound. The preferred conditions are: 1.5 eq. Het, (e.g.morpholine), 1.5 eq. Nat-BuO, 0.08 eq BINAP, 0.04 eq. Pd(dba)₃, intoluene at 100° C. for 18 hrs.

[0227] Step (z): Hydroxylation of compound (XXXV) using a suitableagent, such as OsO₄ or KMnO₄ optionally in the presence of a suitableoxidant (e.g. NMMO) provides the diol (XXXVI). The preferred conditionsare: cat OsO₄, 1.1 eq. NMMO in H₂O:acetone (1:2 by volume) at r.t. for72hrs.

[0228] Step (aa): The aldehyde (XXVIII) may be obtained from the diol(XXXVI) by oxidation, according to the methods described in Synthesis,229 (1974).

[0229] The preferred conditions are: 1.1 eq. NalO₄, in MeCN at r.t. for2 hrs.

[0230] Step (bb): O-alkylation and addition by cyanide is undertakenusing the preferred conditions of 3 eq. Etl, in DCM at rt. for 16 hrs,followed by 2 eq. NaCN in H₂O at 60° C. for 1 hr.

[0231] Step (cc): Condensation with N,N-dimethylformamide dimethylacetalis undertaken using the preferred conditions: Substrate (XLXII) inN,N-dimethylformamide/N,N-dimethylformamide dimethylacetal (1:1 to 1:10by volume) as solvent, at reflux for 8-16 hrs.

[0232] Step (dd): Cyclisation is undertaken using the preferredconditions: substrate (XLIII) in EtOH/48% HBr (about 1:1 by volume) for18 hour.

[0233] Step (ee): Protection of the N atom of (XLIV) followed byreduction is achieved using standard methodology, e.g. PG is Benzyl,followed by reduction of the ring using a suitable reducing agent (e.g.NaBH₄). Preferred conditions are 1.5 eq benzyl bromide, in MeCN atreflux for 2 hours, followed by an excess of NaBH₄ in EtOH at 0° C. tort. for 16 hrs.

[0234] Compound (XLVII) may be further elaborated in a manner analogousto that shown in scheme 4.

[0235] Step (ff): Excess amine (R⁵R⁶NH) is reacted with the bromide(XLVI), optionally in the presence of a 3° amine base (e.g. Hünig'sbase), at elevated temperature and optionally at elevated pressure, forup to 24 hrs leading to formation of compound (XLVIII). Preferably anexcess of amine R⁵R⁶NH (as solvent) is used, at between 140 and 170° C.for up to 20 hrs and optionally at elevated pressure.

[0236] Compound (LI) can then be elaborated according to scheme 16 and17 below. When R⁴ represents NR⁵R⁶ or an N-linked Het:

[0237] Step (gg): Condensation of compound (L) is achieved with asuitable formamidine in the presence of a suitable base (alkali metalalkoxide, or hydride, such as NaOEt, NaH) in a suitable solvent (e.g.EtOH) at elevated temperature. Preferred conditions are: NaOEt,(generated in-situ), carbonyl compound (L), slight excess of(NH₂CH(N)CH₂OH), in EtOH at reflux for 3 hours.

[0238] Step (hh): Alcohol (LI) is reacted, in-situ, to form a suitablealkylating agent (halo, mesylate, tosylate), followed by reaction withan excess of NR⁵R⁶ or an N-linked Het, in the presence of a 3° aminebase (Et₃N, Hünig's base) in a suitable solvent. The preferredconditions are: 1.2 eq. MsCl, 2.5 eq-5 eq. NR⁵R⁶ or an N-linked Het,1.5-2.2 eq. base (Et₃N, Hünig's base) in DCM or tetrahydrofuran for 1-18hrs between r.t. and reflux.

[0239] Step (ii): The aldehyde (LIV) may be obtained by the oxidation ofthe alcohol (LI) according to the method of Swern, (J. Org. Chem. 41,957, 1976). The preferred conditions are: 2 eq. DMSO, 1.1 eq. TFAA, inDCM at −60° C. for 30 mins, followed by 5 eq. Et₃N.

[0240] Compounds of formula (LIV) may be further elaborated usingmethods analogous to those shown in scheme 4, to provide compounds offormula (LIII).

[0241] Step (jj): Condensation of the compound (LV) is undertaken with asuitable formamidine in the presence of a suitable base (alkali metalalkoxide, or hydride, such as NaOEt, NaH) in a suitable solvent (e.g.alcohol, EtOH) at elevated temperature. The preferred conditions are:2.3 eq. NaOEt (generated in-situ), dicarbonyl compound (LV), 1.1 eq.formamidine acetate in EtOH at reflux for 40 hrs.

[0242] Step (kk)-Metalation of compound (LVII) is undertaken followingthe method of Kondo et. al (J. Chem. Soc., Perkin Trans. 1, 1996),followed by quench of the intermediate anion by an excess of formylsource (e.g. N,N-dimethylformamide), to provide compound (LVIII).Preferred conditions are: 1.1 eq Te, 1.12 eq. n-BuLi, tetrahydrofuran atr.t. for 30 mins, then 1.12 eq n-BuLi, excess N,N-dimethylformamide at−78° C. for 45 mins.

[0243] Compounds (LVIII) may then be elaborated further in an analogousmanner to scheme 4.

[0244] Compounds of formula:

[0245] may be prepared by analogy to the methods described in WO02\053558, from readily available starting materials using appropriatereagents and conditions.

[0246] Compounds of formula (LX) may be prepared by analogy to themethods described in JP 07101959, and to those described herein, fromreadily available starting materials using appropriate reagents andreaction conditions.

[0247] Alternatively, they may be prepared according to scheme 19 below,when Het is N-linked:

[0248] Step (mm): Metalation of compound (LXI) is undertaken with asuitable base (e.g. nBuLi) at low temp. (−78° C.), followed by quenchwith bromine, to give compound (LXII). Preferred conditions are: 1.1 eq.nBuLi, in tetrahydrofuran at −78° C. for 15 mins, then 1.1 eq. Bromine.

[0249] Compound (LXIII) may be obtained by reaction with Het, accordingto the methods described previously in step yy.

[0250] Compound (LXIV) may be obtained by reaction of bromide (LXII)with R⁴COH, according to the conditions described previously for step v.

[0251] Compounds of formula (LXV) may be prepared by analogy to themethod described in WO 97/30053, and to those described herein, fromappropriate aminomethylketones, prepared in accordance with the methodof Yinglin and Hongwen, Synthesis 1990; 615, and other readily availablestarting materials.

[0252] Step (nn): Alkylation of compound (LXVI), where PG is a suitableN-protecting group, (preferably Boc or benzyl) is achieved, using asuitable alkylating agent, LR⁴-LG, (where LR⁴ is as previously defined,and LG is a suitable leaving group, preferably halo) in the presence ofa suitable alkali metal base (e.g. NaOH, K₂CO₃) in a solvent such asN,N-dimethylformamide or MeCN, at elevated temperature. The preferredconditions are: 1.2 eq. ZLG, 3 eq. K₂CO₃ in N,N-dimethylformamide at 65°C. for 26 hrs.

[0253] Compounds of formula (I) may also be prepared by the method shownin Scheme 21.

[0254] Step (oo) The acyl guanidine (LXXI) may be prepared by usingeither

[0255] (i) the acid chloride of acid (LXIX) and the anion of theguanidine (LXX) prepared in situ, in the presence of a base such asK^(t)BuO, NaOH, K₂CO₃ or CS₂CO₃ in a suitable solvent e.g. DMF , or

[0256] (ii) the acid (LXIX) with a conventional coupling agent such asCDI or DCC and the guanidine (LXX), in the presence of base such ascaesium carbonate in a suitable solvent e.g. DMF.

[0257] Typically the conditions are as follows:

[0258] (i) acid chloride of acid (LXIX) (generated in-situ), an excessof guanidine (LXX), with an excess of base such as K^(t)BuO or NaH, inDMF, without heating for 1 to 24 hrs, or

[0259] (ii) acid (LXIX), CDI, an excess of guanidine (LXX), with anexcess Cs₂CO₃ in DMF, at room temperature for 12 to 48 hrs.

[0260] Step (pp) Cyclisation of the acyl guanidine (LXXI) to givecompound (I) is accomplished by reaction in the presence of a suitablebase such as NaOH or K^(t)BuO in a suitable high boiling solvent such as3-methyl-pentan-3-ol or ethylene glycol

[0261] Typically the conditions are as follows

[0262] The guanidine (LXXI) with excess potassium t-butoxide in3-methyl-pentan-3-ol under reflux for 1 to 24 hours

[0263] Compounds suitable for use as compound (LXX) may be prepared fromappropriate compounds of formula (III) by the methods shown in Scheme22.

[0264] LG is a suitable leaving group such as SH, SMe, pyrazole orNH-triflyl. Preferred is SMe.

[0265] PG is a nitrogen protecting group such as CBz or boc. Preferredis boc on both nitrogens

[0266] Step (qq) Compound (LXXIII) can be prepared from compounds(LXXII) and (III) by mixing them with a suitable transition metal saltsuch as mercury (II) chloride or silver chloride in the presence of anexcess of tertiary amine base such as Hünig's base or triethylamine in asuitable solvent such as dichloromethane for 1 to 24 hours Preferredconditions are; 1.2 eq. of compound (LXXII) 1.2 eq. mercury (II)chloride, 3 eq. triethylamine in dichloromethane for 16 hours.

[0267] It will be appreciated by one skilled in the art that furtherelaboration of suitable R² groups (for example those containing a“reactive” N atom, which optionally may be part of a ring) may beachieved using standard chemical transformations (for examplealkylation, reduction or reductive amination). Furthermore, it will beappreciated that standard protecting and deprotecting group strategiesmay be employed.

[0268] The following preparations describe the preparation of certainintermediate compounds used for the synthesis of compounds of theformula (I):

[0269] Spectroscopic data were recorded on a Finnigan Mat. Navigator(LRMS, either positive (ES⁺) or negative (ES⁻) electrospray mode), andVarian Unity Inova-400 (NMR, 400 MHz) instruments and are consistentwith the assigned structures. Optical rotations were obtained using aPerkin Elmer 341 polarimeter.

[0270] Combustion analyses were performed by Exeter Analytical (UK)Limited, Uxbridge, Middlesex. Reactions were performed under anatmosphere of dry nitrogen unless otherwise noted. Flash chromatographyrefers to column chromatography on silica gel (Kieselgel 60, 230-400mesh, from E. Merck, Darmstadt). Kieselgel 60 F₂₅₄ plates from E. Merckwere used for TLC, and compounds were visualised using UV light, 5%aqueous potassium permanganate or chloroplatinic acid/potassium iodidesolution.

[0271] In cases where compounds were analysed as hydrates, the presenceof water was evident in the enhanced peak due to water in the NMRspectra. The purity of compounds was carefully assessed using analyticalTLC and proton NMR (400 MHz), and the latter was used to calculate theamount of solvent in solvated samples. In multistep sequences, thepurity and structure of intermediates were verified spectroscopically byNMR and LRMS.

Preparation 12,6-Difluoro-N-(2-hydroxy-1,1-dimethylethyl)-4-methoxybenzamide

[0272]

[0273] The 2,6-difluoro-4-methoxybenzoic acid (Mol. Cryst. Liq. Cryst.1989; 172; 165) (2.09 g, 11.1 mmol) was suspended in dichloromethane(110 mL) and a few drops of N,N-dimethylformamide was added followed byoxalyl chloride (2.79 g, 22.2 mmol). The reaction mixture was stirredfor 45 minutes at room temperature, after which time a clear homogeneoussolution had formed. The reaction mixture was concentrated under reducedpressure and redissolved in dichloromethane (100 mL). The reactionmixture was then added slowly to an ice-cold solution ofamino-2-methylpropanol (3.56 g, 40 mmol), in dichloromethane (50 mL).After stirring at room temperature for 1 hour, the reaction mixture waswashed with water (75 mL), 0.2N hydrochloric acid (50 mL), dried (MgSO₄)and concentrated under reduced pressure to give the title compound as awhite solid (2.77 g, 96%).

[0274] hu 1H-nmr (CDCl₃, 400 MHz) δ: 1.38 (s, 6H), 3.70 (m, 2H), 3.80(s, 3H), 5.90 (bs, 1H), 6.42 (2xs, 2H).

[0275] LRMS: m/z (ES⁺) 260 [MH⁺]

Preparation 22-(2,6-Difluoro-4-methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole

[0276]

[0277] To a solution of the alcohol from preparation 1 (2.75 g, 10.6mmol) in anhydrous dichloromethane (50 mL) was added thionyl chloride(1.43 g, 12 mmol) and the reaction stirred for 1.5 hours at roomtemperature. The reaction mixture was poured into 1M sodium hydroxidesolution (50 mL) and extracted with dichloromethane (2×50 mL). Thecombined organic solutions were dried (MgSO₄) and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (eluting with dichloromethane:methanol 96:4) to give thetitle compound as a clear oil (2.40 g, 94%).

[0278]¹H-nmr (CDCl₃, 400 MHz) δ: 1.40 (s, 6H), 3.80 (s, 3H), 4.04 (s,2H), 6.42 (m, 2H).

[0279] LRMS: m/z (ES⁺) 242 [MH⁺]

Preparation 32-(2-Cyclopropyl-6-fluoro-4-methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole

[0280]

[0281] To a solution of cyclopropyl bromide (12.1 g, 100 mmol) inanhydrous tetrahydrofuran (100 mL) was added magnesium turnings (2.4 g,100 mmol) followed by a crystal of iodine, at room temperature. After afew minutes the reaction initiated and came to reflux without anyadditional heating. When the reflux was complete the reaction was cooledto room temperature and stirred for 2 hours. A solution of the fluorocompound from preparation 2 (9.64 g, 40 mmol) in tetrahydrofuran (50 mL)was cooled in an ice-bath to 0° C., and the grignard solution (50 mL)was added dropwise over 15 minutes, the cooling bath was removed andreaction warmed to room temperature and stirred for 1 hour. Furthergrignard solution (20 mL) was added and stirred for 1 hour. Furthergrignard solution (10 mL) was added and stirred for 1 hour. The reactionmixture was then quenched with 1M citric acid (30 mL), as some solidremained undissolved 2M hydrochloric acid (30 mL) was added. Theresultant mixture was partitioned between ethyl acetate (400 mL) andwater (200 mL), basified with concentrated ammonia solution and theorganic layer separated, washed with water (150 mL), brine (150 mL),dried (MgSO₄) and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel (eluting withhexane:isopropyl alcohol 85:15) to give the title compound as a clearoil (10.32 g, 98%).

[0282]¹H-nmr (CDCl₃, 40 MHz) δ: 0.66 (m, 2H), 0.94 (m, 2H), 1.40 (s,6H), 2.18 (m, 1H), 3.78 (s, 3H), 4.07 (s, 2H), 6.25 (s, 1H), 6.42 (m,1H).

[0283] LRMS: m/z (ES⁺) 286 [MNa⁺]

Preparation 42-(2-Cyclobutyl-6-fluoro-4-methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole

[0284]

[0285] To a solution of cyclobutyl chloride (5.64 g, 62 mmol) inanhydrous tetrahydrofuran (60 mL) was added magnesium turnings (1.56 g,65 mmol) followed by a crystal of iodine, at room temperature. Themixture was stirred at room temperature for 1 hour, followed by afurther hour under reflux. A solution of the fluoro compound frompreparation 2 (7.23 g, 30 mmol) in tetrahydrofuran (80 mL) was cooled inan ice-bath to 0° C., and the grignard solution (40 mL) was addeddropwise over 15 minutes, the cooling bath was removed and reactionwarmed to room temperature and stirred for 2 hours. Further grignardsolution (10 mL) was added and the reaction stirred for a further 30minutes. The reaction was poured into a solution ofethylenediaminetetraacetic acid disodium salt (12 g) in 1N sodiumhydroxide (100 mL), and the mixture extracted with ethyl acetate (1×200mL, 2×100 mL). The combined organic extracts were dried (MgSO₄) andevaporated under reduced pressure, to afford the title compound as apale yellow oil, 8.31 g.

[0286]¹H-nmr (CDCl₃, 40 MHz) δ: 1.43 (s, 6H), 1.77-1.88 (m, 1H),1.91-2.07 (m, 1H), 2.07-2.20 (m, 2H), 2.24-2.36 (m, 2H), 3.82 (s, 3H),3.83 (m, 1H), 4.10 (s, 2H), 6.48 (dd, 1H), 6.66 (d, 1H).

[0287] LRMS: m/z (APCl⁺) 278 [MNH₄ ⁺]

Preparation 52-(2-Cyclohexyl-6-fluoro-4-methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole

[0288]

[0289] Cyclohexylmagnesium chloride (22 mL, 2M in diethyl ether, 44mmol) was added slowly to an ice-cooled solution of the compound frompreparation 2 (9.64 g, 40 mmol) in tetrahydrofuran (100 mL), and thesolution then stirred at room temperature for 2 hours. Water (10 mL) wasadded, the mixture poured into ethyl acetate, and washed with a solutionof ethylenediaminetetracetic acid disodium salt (24 g) in water (200mL), then 1N sodium hydroxide solution (100 mL) and brine. The organicsolution was dried (MgSO₄) and evaporated under reduced pressure toafford the title compound as a colourless oil, 12.4 g.

[0290]¹H-nmr (CDCl₃, 400 MHz) δ: 1.15-1.50 (m, 10H), 1.76 (d, 2H), 1.84(m, 2H), 1.90 (m, 2H), 2.86 (m, 1H), 3.80 (s, 3H), 4.13 (s, 2H), 6.47(dd, 1H), 6.63 (d, 1H).

[0291] LRMS: m/z (APCl⁺) 306 [MH⁺]

Preparation 6 2-Cyclopropyl-6-fluoro-4-methoxybenzonitrile

[0292]

[0293] Pyridine (31.6 g, 400 mmol) was added to a solution of thecompound from preparation 3 (10.32 g, 39.2 mmol) in ethyl acetate (150mL), followed by phosphorous oxychloride (12.27 g, 80 mmol ). Thereaction was stirred at reflux for 5 hours, cooled and poured onto ice.This aqueous mixture was extracted with ethyl acetate, the organicsolution washed with 2M hydrochloric acid, and brine then dried (MgSO₄)and evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel using dichloromethane to afford thetitle compound as a white solid, 6.41 g.

[0294]¹H-nmr (CDCl₃, 400 MHz) δ: 0.88 (m, 2H), 1.16 (m, 2H), 2.20 (m,1H), 3.80 (s, 6H), 6.21 (s, 1H), 6.49 (m, 1H).

[0295] LRMS: m/z (ES⁺) 214 [MNa⁺]

Preparation 7 2-Cyclobutyl-6-fluoro-4-methoxybenzonitrile

[0296]

[0297] The title compound was obtained as a pale yellow oil in 99% yieldfrom the compound from preparation 4, following a similar procedure tothat described in preparation 6, except the compound was isolatedwithout column chromatography.

[0298]¹H-nmr (CDCl₃, 400 MHz) δ: 1.78-1.94 (m, 1H), 1.99-2.24 (m, 3H),2.41-2.55 (m, 2H), 3.81 (m, 1H), 3.87 (s, 3H), 6.53 (dd, 1H), 6.69 (d,1H).

[0299] LRMS: m/z (APCl⁺) 223 [MNH₄ ⁺]

Preparation 8 2-Cyclohexyl-6-fluoro-4-methoxybenzonitrile

[0300]

[0301] The title compound was obtained as a colourless oil in 93% yieldfrom the compound from preparation 5, following a similar procedure tothat described in preparation 6.

[0302]¹H-nmr (CDCl₃, 400 MHz) δ: 1.18-1.57 (m, 4H), 1.73-1.96 (m, 6H),2.85-2.96 (m, 1H), 3.85 (s, 3H), 6.54 (dd, 1H), 6.65 (d, 1H).

[0303] LRMS: m/z (APCl⁺) 251 [MNH₄ ⁺]

Preparation 9 2-Amino-6-cyclopropyl-4-methoxybenzonitrile

[0304]

[0305] The fluoro compound from preparation 6 (3.0 g, 15.7 mmol) wasadded to a saturated solution of 0.88 ammonia in dimethylsulphoxide (20mL), and the solution stirred in a sealed vessel for 18 hours at 150° C.The cooled mixture was partitioned between ethyl acetate and water andthe layers separated. The organic phase was dried (MgSO₄) and evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel using dichloromethane as eluant to affordthe title compound as a white crystalline solid, 1.28 g.

[0306]¹H-nmr (CDCl₃, 400 MHz) δ: 0.74 (m, 2H), 1.02 (m, 2H), 2.10 (m,1H), 3.76 (s, 6H), 4.38 (bs, 2H), 5.82 (s, 1H), 6.00 (s, 1H).

[0307] LRMS: m/z (ES⁺) 211 [MNa⁺]

Preparation 10 2-Amino-6-cyclobutyl-4-methoxybenzonitrile

[0308]

[0309] The title compound was obtained as a white solid in 54% yieldfrom the fluoro compound from preparation 7, following a similarprocedure to that described in preparation 9, exceptdichloromethane:ethyl acetate (100:0 to 80:20) was used as the columneluant.

[0310]¹H-nmr (CDCl₃, 400 MHz) δ: 1.76-1.90 (m, 1H), 1.94-2.21 (m, 3H),2.37-2.49 (m, 2H), 3.66-3.77 (m, 1H), 3.80 (s, 3H), 4.06-4.43 (bs, 2H),6.05 (s, 1H), 6.27 (s, 1H).

[0311] LRMS: m/z (ES⁺) 225 [MNa⁺]

Preparation 11 2-Amino-6-cyclohexyl-4-methoxybenzonitrile

[0312]

[0313] The title compound was obtained as a yellow solid in 44% yieldfrom the fluoro compound from preparation 8, following the proceduredescribed in preparation 9.

[0314]¹H-nmr (CDCl₃, 400 MHz) δ: 1.17-1.53 (m, 5H), 1.72-1.96 (m, 5H),2.80 (m, 1H), 3.78 (s, 3H), 6.05 (d, 1H), 6.22 (d, 1H).

[0315] LRMS: m/z (APCl⁺) 231 [MH⁺]

Preparation 12 5-Cyclopropyl-7-methoxy-2,4(1H,3H)-quinazolinedione

[0316]

[0317] A solution of the compound from preparation 9 (1.25 g, 6.65 mmol)in N,N-dimethylformamide (10 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene(2 mL) was cooled to −78° C., and solid carbon dioxide added. Thereaction vessel was sealed and heated to 140° C. for 18 hours. Thecooled mixture was poured into water (150 mL), then acidified using 2Nhydrochloric acid, and the mixture stirred for 10 minutes. The resultingprecipitate was filtered off, washed with water and acetone, to affordthe title compound as a white solid, 1.44 g.

[0318]¹H-nmr (DMSOd₆, 400 MHz) δ: 0.68 (m, 2H), 0.95 (m, 2H), 3.40 (m,1H), 3.76 (s, 3H), 6.18 (s, 1H), 6.42 (s, 1H).

[0319] LRMS: m/z (ES⁻) 231 [M−H⁻]

Preparation 13 5-Cyclobutyl-7-methoxy-2,4(1H,3H)-quinazolinedione

[0320]

[0321] The title compound was obtained as an off-white solid in 75%yield, from the compound from preparation 10, following the proceduredescribed in preparation 12.

[0322]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.72 (m, 1H), 1.81-2.05 (m, 3H), 2.29(m, 2H), 3.81 (s, 3H), 4.45 (m, 1H), 6.50 (d, 1H), 6.62 (d, 1H), 10.79(s, 1H), 10.85 (s, 1H).

[0323] LRMS: m/z (APCl⁻) 245 [M−H⁻]

Preparation 14 5-Cyclohexyl-7-methoxy-2,4(1H,3H)-quinazolinedione

[0324]

[0325] The title compound was obtained as a white solid in 77% yield,from the compound from preparation 11, following the procedure describedin preparation 12.

[0326]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.14-1.45 (m, 5H), 1.63-1.82 (m, 5H),3.78 (s, 3H), 4.08 (t, 1H), 6.50 (d, 1H), 6.58 (d, 1H), 10.80 (s, 1H),10.85 (s, 1H).

[0327] LRMS: m/z (APCl⁻) 273 [M−H⁻]

Preparation 15 2,4-Dichloro-5-cyclopropyl-7-quinazolinyl methyl ether

[0328]

[0329] To a solution of the compound from preparation 12 (3.87 g, 16.7mmol) in phosphorous oxychloride (50 mL) was addedN,N-diisopropylethylamine (5.17 g, 40 mmol). The reaction mixture washeated at 100° C. for 1 hour, at reflux for 6 hours then cooled to roomtemperature. The phosphorous oxychloride was removed under reducedpressure. The resultant oil was partitioned between ethyl acetate (500mL) and ice-water (300 mL), the layers were separated, the organic phasewashed with 1M hydrochloric acid (100 mL), brine (100 mL), dried (MgSO₄)and concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel eluting with a solvent gradient ofdichloromethane:ethyl acetate (100:0 to 94:6) to give the title compoundas a white solid (3.97 g, 88%).

[0330]¹H-nmr (CDCl₃, 400 MHz) δ: 0.84 (m, 2H), 1.17 (m, 2H), 2.70 (m,1H), 2.94 (s, 3H), 7,10 (s, 1H), 7.14 (s, 1H).

[0331] LRMS: m/z (ES⁺) 291 [MNa⁺]

Preparation 16 2,4-Dichloro-5-cyclobutyl-7-quinazolinyl methyl ether

[0332]

[0333] To a solution of the compound from preparation 13 (2.46 g, 10mmol) in phosphorous oxychloride (25 mL) was addedN,N-diisopropylethylamine (3.1 g, 24 mmol) and the reaction mixture washeated at reflux for 7 hours then cooled to room temperature. Thesolution was poured cautiously onto ice, diluted with water, and themixture extracted with dichloromethane (3×100 mL). The combined organicsolutions were dried (MgSO₄) and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel elutingwith a solvent gradient of dichloromethane:ethyl acetate (100:0 to 94:6)to give the title compound as a white solid, 1.74 g.

[0334]¹H-nmr (CDCl₃, 400 MHz) δ: 1.84-1.94 (m, 1H), 2.00-2.23 (m, 3H),2.49-2.60 (m, 2H), 3.97 (s, 3H), 4.60 (m, 1H), 7.14 (d, 1H), 7.27 (d,1H).

[0335] LRMS: m/z (ES⁺) 305 [MNa⁺]

Preparation 17 2,4-Dichloro-5-cyclohexyl-7-quinazolinyl methyl ether

[0336]

[0337] The title compound was obtained as a white solid in 64% yield,from the compound from preparation 14, following the procedure describedin preparation 16.

[0338]¹H-nmr (CDCl₃, 400 MHz) δ: 1.21-1.60 (m, 5H), 1.73-2.07 (m, 5H),3.96 (s, 3H), 4.05 (m, 1H), 7.16 (d, 1H), 7.23 (d, 1H).

[0339] LRMS: m/z (APCl⁺) 311 [MH⁺]

Preparation 18 2-Chloro-5-cyclopropyl-7-methoxy-4(3H)-quinazolinone

[0340]

[0341] 1N Sodium hydroxide solution (30 mL) was added to a solution ofthe chloro compound from preparation 15 (2.2 g, 8.18 mmol) in dioxane(50 mL) and the reaction stirred at room temperature for 2 hours. Thereaction was acidified using 2M hydrochloric acid and extracted withdichloromethane:methanol (95:5) (3×150 mL). The combined organicsolutions were dried (MgSO₄) and evaporated under reduced pressure togive the title compound as a white solid, 1.85 g.

[0342]¹H-nmr (CDCl₃, 400 MHz) δ: 0.73 (m, 2H), 1.09 (m, 2H), 3.31 (m,1H), 3.86 (s, 3H), 6.60 (d, 1H), 6.89 (d, 1H).

[0343] LRMS: m/z (ES⁺) 273 [MNa⁺]

Preparation 19 2-Chloro-5-cyclobutyl-7-methoxy-4(3H)-quinazolinone

[0344]

[0345] 2M Sodium hydroxide solution (12.5 mL, 25 mmol) was added to asolution of the dichloride from preparation 16 (1.71 g, 6.04 mmol) indioxane (50 mL), and the solution stirred at room temperature for 8hours. The mixture was acidified using 2M hydrochloric acid (20 mL), theresulting precipitate filtered off, washed with water, acetone anddiethyl ether, and dried in vacuo, to afford the title compound, 1.26 g.

[0346]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.69-1.79 (m, 1H), 1.86-2.10 (m, 3H),2.27-2.38 (m, 2H), 3.87 (s, 3H), 4.51 (m, 1H), 6.90 (d, 1H), 6.94 (d,1H), 12.83 (bs, 1H).

[0347] LRMS: m/z (ES⁺) 287 [MNa⁺]

Preparation 20 2-Chloro-5-cyclohexyl-7-methoxy-4(3H)-quinazolinone

[0348]

[0349] The title compound was obtained as a white solid in 96% yield,after trituration with diethyl ether, from the dichloride frompreparation 17, following a similar procedure to that described inpreparation 18.

[0350]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.14-1.47 (m, 5H), 1.66-1.84 (m, 5H),3.85 (s, 3H), 4.13 (m, 1H), 6.88 (d, 1H), 6.90 (d, 1H), 12.84 (bs, 1H).LRMS: m/z (ES⁺) 293 [MH⁺]

Preparation 21 3-Methoxyazetidine hydrochloride

[0351]

[0352] 1N Ethereal hydrochloric acid was added to a solution of1-(diphenylmethyl)-3-methoxyazetidine (WO 9613502) (1.3 g, 5.14 mmol) indichloromethane (10 mL), until a precipitate formed, and the mixtureevaporated under reduced pressure. The residual foam was re-dissolved inmethanol (75 mL), 10% palladium on charcoal (900 mg) and ammoniumformate (6.5 g) added, and the mixture heated under reflux for 30minutes. The cooled mixture was filtered through Arbocel®, the filtrateevaporated under reduced pressure, and the residue partitioned betweendichloromethane and water. The layers were separated, the aqueous phaseacidified using 1N hydrochloric acid, and the solution evaporated underreduced pressure. The residual solid was triturated with ethanol andthen dichloromethane, and the solid filtered off. The filtrate wasevaporated under reduced pressure to give the title compound as a yellowoil, 130 mg.

[0353]¹H-nmr (CDCl₃, 400 MHz) δ: 3.22 (bs, 3H), 3.88 (m, 2H), 4.10 (m,2H), 4.26 (m, 1H).

Preparation 22 tert-Butyl5-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0354]

[0355] A solution of di-tert-butyl dicarbonate (66.75 g, 0.31 mol) wassuspended in 1M sodium hydroxide solution (200 mL) and 1,4-dioxane (300mL) under nitrogen gas. A solution of 1,2,3,4-tetrahydro-5-isoquinolinol(20.0 g, 134 mmol) in 1,4-dioxane (100 mL) was added and the resultingsuspension stirred at room temperature for 16 hours. The reactionmixture was concentrated under reduced pressure, and the residuepartitioned between IM hydrochloric acid (300 mL) and dichloromethane(500 mL). The aqueous phase was re-extracted with dichloromethane (200mL). The combined organic extracts were dried (MgSO₄) and concentratedunder reduced pressure to give an orange oil. The crude product wasdissolved in 1,4-dioxane (200 mL) and methanol (100 mL) under nitrogengas followed by the addition of 2N sodium hydroxide solution (150 mL)and the resulting cloudy mixture was stirred at room temperature for 3hours. The reaction mixture was concentrated under reduced pressure, andthe residue partitioned between ethyl acetate (600 mL) and water (200mL). The organic phase was separated, washed with 2N hydrochloric acid(200 mL), brine (250 mL) then dried (MgSO₄) and concentrated underreduced pressure to give a tan solid. The solid was suspended indichloromethane (150 mL) then pentane added (800 mL) and filtered togive the title compound as a white solid (32.04 g, 84%).

[0356]¹H-nmr (CDCl₃, 300 MHz) δ: 1.49 (s, 9H), 2.76 (t, 2H), 3.66 (t,2H), 4.56 (s, 2H), 5.29 (bs, 1H), 6.67 (dd, 2H), 7.05 (dd, 1H).

[0357] LRMS: m/z (ES⁺) 272 [MNa⁺].

[0358] Microanalysis: Found: C, 67.30; H, 7.68; N, 5.61. C₁₄H₁₉NO₃requires C, 67.45; H, 7.68; N, 5.62%

Preparation 23tert-Butyl5-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0359]

[0360] Triethylamine (20.1 mL, 144 mmol) was added to a suspension ofthe compound from preparation 22 (32.65 g, 131 mmol) in dichloromethane(400 mL) under nitrogen gas. The mixture was cooled to 0° C. andN-phenylbistrifluoromethanesulfonamide (51.46 g, 144 mmol) was addedportionwise. The resulting brown solution was allowed to warm to roomtemperature and stirred for 16 hours. The reaction mixture was washedconsecutively with water (200 mL), 0.5M hydrochloric acid (200 mL),brine (250 mL) and then dried (MgSO₄) and concentrated under reducedpressure to give a brown oil. The crude product was purified by columnchromatography on silica gel eluting with a solvent gradient ofn-pentane:diethyl ether (100:0 to 70:30). The product was co-evaporatedwith dichloromethane (2×100 mL) to give the title compound as acolourless gum (40.1 g, 80%).

[0361]¹H-nmr (CDCl₃, 300 MHz) δ: 1.49 (s, 9H), 2.89 (t, 2H), 3.65 (t,2H), 4.59 (s, 2H), 7.13 (m, 2H), 7.24 (dd, 1H). LRMS: m/z (ES⁺) 404[MNa⁺].

Preparation 24 tert-Butyl5-cyano-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0362]

[0363] The compound from preparation 23 (20.0 g, 52 mmol) was dissolvedin N,N-dimethylformamide (120 mL) under nitrogen gas. Zinc cyanide (6.15g, 52 mmol), lithium chloride (2.22 g, 52 mmol) andtetrakis(triphenylphosphine)palladium (0) (2.42 g, 2.1 mmol) were addedand the mixture heated at 110° C. for 8 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue partitioned betweendichloromethane (500 mL) and saturated sodium bicarbonate solution (250mL). The aqueous phase was re-extracted with dichloromethane (300 mL).The combined organic solutions were dried (MgSO₄) and concentrated underreduced pressure to give a golden oil. The crude product was purified bycolumn chromatography on silica gel using n-pentane:ethyl acetate(90:10) as eluant. The product was co-evaporated with dichloromethane(2×100 mL) to give the title compound as a colourless oil (13.32 g,49%).

[0364]¹H-nmr (CDCl₃, 300 MHz) δ: 1.48 (s, 9H), 3.02 (t, 2H), 3.70 (t,2H), 4.58 (s, 2H), 7.20-7.35 (m, 2H), 7.50 (d, 1H).

[0365] LRMS: m/z (ES⁺) 281 [MNa⁺].

Preparation 25 tert-Butyl5-formyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0366]

[0367] A solution of the compound from preparation 24 (9.1 g, 35 mmol)in toluene (100 mL) was cooled to −78° C. under nitrogen gas. Over 1hour, diisobutylaluminium hydride (80 mL of a 1M solution in toluene, 80mmol) was added dropwise keeping the internal temperature below −60° C.and the resulting mixture stirred for 2 hours at −78° C. Methanol (20mL) was pre-cooled to −78° C. and the added dropwise to the reactionmixture keeping the internal temperature below −60° C. Over 20 mins thereaction mixture was poured into 1N hydrochloric acid (200 mL) that hadbeen pre-cooled to 0° C. The reaction mixture was extracted with ethylacetate (3×400 mL) and the combined organic extracts were washed withbrine (200 mL), dried (MgSO₄) and concentrated under reduced pressure.The product was co-evaporated with dichloromethane (2×50 mL) to give thetitle compound as a yellow oil (8.14 g, 88%).

[0368]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.40 (s, 9H), 3.19 (t, 2H), 3.55 (t,2H), 4.55 (s, 2H), 7.40 (dd, 2H), 7.47 (d, 1H), 7.70 (d, 1H).

[0369] LRMS: m/z (ES⁺) 284 [MNa⁺].

Preparation 26 1-Benzyl-4-(1-pyrrolidinyl)-1,2,3,6-tetrahydropyridine

[0370]

[0371] Pyrrolidine (31.8 mL, 0.38 mol) was added to a solution of1-benzyl-4-piperidinone (48.0 g, 0.25 mol) in toluene (180 mL) and themixture refluxed under Dean-Stark conditions for 4.5 hours. The reactionmixture was allowed to cool to room temperature and concentrated underreduced pressure to give the title compound as an orange oil (61.8 g,100%).

[0372]¹H-nmr (400 MHz, CDCl₃) δ: 1.80-1.84 (m, 4H), 2.32 (m, 2H), 2.59(t, 2H), 3.02 (4Hm,), 3.07 (s, 2H), 3.57 (s, 2H), 4.18 (s, 1H),7.22-7.30 (m, 3H), 7.35-7.36 (d, 2H).

Preparation 27 6-Benzyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2(1H)-one

[0373]

[0374] A mixture of the compound from preparation 26 (61.50 g, 0.25 mol)and propiolamide (J. Am. Chem. Soc. 1988; 110; 3968) (35.05 g, 0.51 mol)were heated under reflux in toluene (500 mL) under nitrogen gas for 16hours. The reaction mixture was allowed to cool to room temperature andconcentrated under reduced pressure. The residue was partitioned betweendichloromethane (800 mL) and saturated sodium bicarbonate solution (400mL). The aqueous phase was further extracted with dichloromethane (3×500mL). The combined organic solutions were dried (MgSO₄) and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol (100:0 to 95:05) to give the title compound asan orange solid (27.71 g, 45%).

[0375]¹H-nmr (DMSOd₆, 400 MHz) δ: 2.53 (t, 2H), 2.63 (t, 2H), 3.24 (s,2H), 3.60 (s, 2H), 6.06 (d, 1H), 7.08 (d, 1H), 7.24 (m, 1H), 7.30 (m,4H).

[0376] LRMS: m/z (ES⁺) 263 [MNa⁺].

Preparation 28 6-Benzyl-2-bromo-5,6,7,8-tetrahydro[1,6]naphthyridine

[0377]

[0378] The compound from preparation 27 (9.51 g, 31 mmol) was suspendedin acetonitrile (45 mL) and anisole (45 mL). Phosphorous oxybromide(44.8 g, 156 mmol) was added portionwise and the mixture heated for 1hour at 120° C. The reaction was allowed to cool to room temperature andthen poured onto ice (400 g). Dichloromethane (400 mL) was added and themixture was then neutralised with saturated sodium carbonate solution(450 mL). The organic layer was collected and the aqueous layerextracted with dichloromethane (500 mL). The combined organic solutionswere dried (MgSO₄) and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel eluting with asolvent gradient of dichloromethane:methanol (100:0 to 97:03) to givethe title compound as a brown oil (5.79 g, 61%).

[0379]¹H-nmr (CDCl₃, 400 MHz) δ: 2.83 (t, 2H), 3.03 (t, 2H), 3.56 (s,2H), 3.70 (s, 2H), 7.12 (d, 1H), 7.21 (d, 1H), 7.26-7.36 (m, 5H).

[0380] LRMS: m/z (ES⁺) 303 [MH⁺].

Preparation 29a6-Benzyl-5,6,7,8-tetrahydro[1,6]naphthyridine-2-carbaldehyde

[0381]

[0382] The bromide from preparation 28 (3.00 g, 9.90 mmol) was dissolvedin tetrahydofuran (70 mL) and cooled to −78° C. n-Butyl lithium (5.5 mLas a 2.5M solution in hexanes, 13.8 mmol) was added and the reactionstirred for a 5 minutes. N,N-Dimethylformamide (2.3 mL, 29.7 mmol) wasthen added and the reaction stirred for 1 hour, the cooling bath removedand the reaction quenched by the addition of saturated potassiumdihydrogenphosphate solution (100 mL). The residue was purified by flashchromatography on silica gel eluting with dichloromethane: methanol(98:2) to give the title compound as a tan solid (2.10 g, 85%).

[0383]¹H-nmr (DMSOd₆, 400 MHz) δ: 2.92 (m, 2H), 3.15 (m, 2H), 3.71 (s,2H), 3.75 (s, 2H), 7.26-7.38 (m, 5H), 7.45 (d, 1H), 7.73 (d, 1H), 10.02(s, 1H).

[0384] LRMS: m/z (ES⁺) 275 [MNa⁺].

Preparation 29b6-Benzyl-5,6,7,8-tetrahydro[1,6]naphthyridine-2-carbaldehyde

[0385]

[0386] A solution of sodium periodate (4.38 g, 20.5 mmol) in water (38ml) was added dropwise to a solution of the diol from preparation 154(7.2 g, 18.7 mmol) in acetonitrile (200 ml), and the reaction wasstirred at room temperature for 2 hours. The mixture was partitionedbetween ethyl acetate (300 ml) and water (300 ml), containing a smallvolume of brine, and the layers separated. The aqueous phase was furtherextracted with ethyl acetate (2×100 ml), and the combined organicsolutions dried over magnesium sulphate and concentrated under reducedpressure, co-evaporating with tetrahydrofuran. The residual oil waspurified by column chromatography on silica gel using an elutiongradient of dichloromethane: ethyl acetate (80:20 to 50:50) to affordthe title compound, as an oil that crystallised on standing (1.3 g).

[0387]¹H-nmr (CDCl₃, 400 MHz) δ: 2.90 (t, 2H), 3.16 (t, 2H), 3.69 (s,2H), 3.74 (s, 2H), 7.23-7.39 (m, 5H), 7.42 (d, 1H), 7.72 (d, 1H), 10.00(s, 1H).

[0388] LRMS: m/z (ES⁺) 275 [MNa⁺]

Preparation 30 3-Methylisonicotinonitrile

[0389]

[0390] To a solution of 3-picoline N-oxide (60 g, 0.55 mol) indichloromethane (1000 mL) was added ethyl iodide (132 mL, 1.65 mol) andthe mixture stirred at room temperature for 16 hours. The precipitatewas collected by filtration and washed with diethyl ether (200 mL) togive a white solid. The solid was dissolved in water (600 mL) and warmedto 50° C. Sodium cyanide (50 g, 1.02 mol) was added as a solution inwater (180 mL) over 1 hour, keeping the internal temperature below 60°C. and the resulting dark brown solution was stirred at 55° C. for afurther 1 hour. The reaction mixture was extracted with diethyl ether(3×600 mL). The combined organic extracts were dried (MgSO₄) andconcentrated under reduced pressure to give a brown oil. The crudeproduct was purified by column chromatography on silica gel eluting witha solvent gradient of n-pentane:dichloromethane (40:60 to 0:100). Theproduct was co-evaporated with dichloromethane (2×300 mL) to give thetitle compound as a colourless oil (30.5 g, 47%).

[0391]¹H-nmr (CDCl₃, 400 MHz) δ: 2.55 (s, 3H), 7.47 (d, 1H), 8.60 (d,1H), 8.67 (s, 1H).

Preparation 31 3-[(E)-2-(Dimethylamino)ethenyl]isonicotinonitrile

[0392]

[0393] A mixture of the nitrile from preparation 30 (30.49 g, 0.26 mol)in N,N-dimethylformamide dimethyl acetal (200 mL) andN,N-dimethylformamide (200 mL) under nitrogen gas was heated underreflux for 16 hours. The reaction mixture was concentrated under reducedpressure to give a brown solid. The crude product was dissolved indichloromethane (100 mL) and n-pentane added until a precipitate formed.The solid was collected by filtration, washed with n-pentane and driedunder reduced pressure to give the title compound as a green solid (25.1g, 56%).

[0394]¹H-nmr (CDCl₃, 400 MHz) δ: 2.95 (s, 6H), 5.23 (d, 1H), 7.24 (d,1H), 8.15 (d, 1H), 8.70 (s, 1H). LRMS: m/z (ES⁺) 174 [MH⁺]

Preparation 32 [2,6]Naphthyridin-1(2H)-one

[0395]

[0396] 48% Hydrobromic acid (97 mL, 578 mmol) was added over 20 minutes,to a solution of the compound from preparation 31 (10.0 g, 57.8 mmol) inethanol (100 mL), and the reaction heated under reflux for 18 hours. Thecooled mixture was filtered, and the collected solid was washed withethanol (25 mL), and dried in vacuo, to afford the title compound asfine yellow crystals, 8.54 g.

[0397]¹H-nmr (DMSOd6, 400 MHz) δ: 6.65 (d, 1H), 7.30 (d, 1H), 7.98 (d,1H), 8.60 (d, 1H), 9.06 (s, 1H), 11.60 (bs, 1H). LRMS: m/z (ES⁺) 147.5[MH⁺]

Preparation 33 6-Benzyl-5,6,7,8-tetrahydro[2,6]naphthyridin-1(2H)-one

[0398]

[0399] To a suspension of the compound from preparation 32 (20.0 g, 0.14mol) in acetonitrile (350 mL) under nitrogen gas was added benzylbromide (24.4 mL, 0.21 mol) and the reaction heated under reflux for 2hours. After the reaction mixture had cooled to room temperature it wasconcentrated under reduced pressure to give a brown oil which wasre-dissolved in ethanol (500 mL). This solution was cooled to 0° C. andsodium borohydride (25.9 g, 0.69 mol) added portionwise over 30 min andthen stirred at 0° C. for 1 hour, followed by stirring at roomtemperature for a further 16 hours. The reaction mixture was cooled to0° C. and 6M hydrochloric acid (200 mL) was added dropwise over 30minutes and then stirred at room temperature for 90 minutes. Theresulting precipitate was filtered off, and the aqueous filtrate wasbasified with 2M sodium hydroxide (1000 mL). With stirring, ethylacetate (250 mL) and then cyclohexane (250 mL) were added and theresulting precipitate collected by filtration to give the title compoundas a light yellow solid (15.50 g, 53%).

[0400]¹H-nmr (DMSOd₆, 400 MHz) δ: 2.27 (t, 2H), 2.60 (t, 2H), 3.28 (s,2H), 3.62 (s, 2H), 5.87 (d, 1H), 7.10 (d, 1H), 7.21-7.25 (m, 5H), 11.23(bs, 1H).

[0401] LRMS: m/z (ES⁺) 241 [MH⁺].

Preparation 34 2-Benzyl-5-bromo-1,2,3,4-tetrahydro[2,6]naphthyridine

[0402]

[0403] Phosphorous oxybromide (74.57 g, 260 mmol) was added portionwiseto a suspension of the compound from preparation 33 (15.5 g, 64.6 mmol)anisole (200 mL) and acetonitrile (100 mL), and the solution stirredunder reflux for 4 hours. The cooled mixture was poured onto ice (500 g)and diluted with dichloromethane (500 mL). The mixture was slowlyneutralised using saturated sodium bicarbonate solution, the phaseseparated, and the aqueous layer extracted with further dichloromethane(500 mL). The combined organic solutions were dried (MgSO₄) andevaporated under reduced pressure to give a green oil. The crude productas purified by column chromatography on silica gel using an elutiongradient of ethyl acetate:pentane (50:50 to 60:40), and repeated usingdiethyl ether:pentane (50:50) to afford the title compound as a whitesolid, 17.4 g.

[0404]¹H-nmr (CDCl₃, 400 MHz) δ: 2.79 (m, 4H), 3.55 (s, 2H), 3.67 (s,2H), 6.85 (d, 1H), 7.23-7.33 (m, 5H), 8.06 (d, 1H).

[0405] LRMS: m/z (ES⁺) 326 [MNa⁺]

Preparation 356-Benzyl-5,6,7,8-tetrahydro[2,6]naphthyridine-1-carbaldehyde

[0406]

[0407] The compound from preparation 34 (3.2 g, 10.6 mmol) was dissolvedin dry tetrahydrofuran (80 mL) under nitrogen gas and cooled to −78° C.n-Butyl lithium (7.3 mL as a 1.6M solution in hexanes, 11.6 mmol) wasadded dropwise over 3 minute s and the reaction stirred for a further3minutes. N,N-Dimethylformamide (2.5 mL, 31.8 mmol) was then added, thereaction stirred for 15 minutes and the cooling bath removed and thereaction stirred for a further 15 minutes before being quenched by water(20 mL). The reaction mixture was partitioned between ethyl acetate (250mL) and water (100 mL). The organic phase was separated, washed withwater (100 mL), brine (100 mL) then dried (MgSO₄) and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel eluting with a solvent gradient of dichloromethane:methanol(100:0 to 80:20) to give the title compound as an orange semi-solid(1.27 g, 48%).

[0408]¹H-nmr (CDCl₃, 400 MHz) δ: 2.77 (t, 2H), 3.30 (t, 2H), 3.62 (s,2H), 3.67 (s, 2H), 7.08 (d, 1H), 7.23-7.35 (m, 5H), 8.50 (d, 1H), 10.15(s, 1H).

[0409] LRMS: m/z (ES⁺) 275 [MNa⁺]

Preparation 36tert-Butyl-3-[(dimethylamino)methylene]-4-oxo-1-piperidinecarboxylate

[0410]

[0411] Tert-butyl-4-oxo-1-piperidinecarboxylate (10 g, 50 mmol) andN,N-dimethylformamide dimethyl acetal (7.3 mL, 55 mmol) were added toN,N-dimethylformamide (75 mL) under nitrogen gas and the mixture heatedat 90° C. for 8 hours and then stirred for a further 16 hours at roomtemperature. The reaction mixture was concentrated under reducedpressure, and the residue partitioned between ethyl acetate (200 mL) andbrine (200 mL). The aqueous phase was re-extracted with ethyl acetate(200 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated under reduced pressure to give a brown oil that solidifiedon standing. Trituration with cyclohexane (20 mL) gave the titlecompound as a light brown solid (8.5 g, 67%).

[0412]¹H-NMR (400 MHz, CDCl₃) δ: 1.45 (s, 9H), 2.42 (t, 2H), 3.06 (s,6H), 3.59 (t, 2H), 4.54 (s, 2H), 7.43 (s, 1H).

[0413] LRMS: m/z (ES⁺) 277 [MNa⁺].

Preparation 37 tert-Butyl2-(hydroxymethyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0414]

[0415] Sodium metal (414 mg, 16.5 mmol) was added to ethanol (42 mL) andstirred at room temperature under nitrogen gas until a clear solutionhad formed. The compound from preparation 24 (4.2 g, 16.5 mmol) and2-hydroxyethanimidamide (J. Am. Chem. Soc.; 68; 1946; 2394) (2 g, 18mmol) were added and the reaction mixture heated under reflux for 3hours and then allowed to cool to room temperature and partitionedbetween ethyl acetate (100 mL) and saturated sodium bicarbonate solution(100 mL). The aqueous phase was re-extracted with ethyl acetate (50 mL).The combined organic extracts were dried (Na₂SO₄) and concentrated underreduced pressure to give a brown oil which was purified by columnchromatography on silica gel eluting with a solvent gradient of ethylacetate : methanol (100:0 to 97:03) to give the title compound as abrown oil (3.00 g, 73%).

[0416]¹H-NMR (400 MHz, CDCl₃) δ: 1.49 (s, 9H), 2.95 (t, 2H), 3.46 (bs,1H), 3.75 (t, 2H), 4.59 (s, 2H), 4.77 (d, 2H), 8.44 (s, 1H).

Preparation 387-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one

[0417]

[0418] Sodium metal (10.1 g, 0.44 mol) was added to ethanol (520 mL) andstirred at room temperature under nitrogen gas until a clear solutionhad formed. Ethyl-3-oxo-N-benzylpiperidine-4-carboxylate hydrochloride(56.5 g, 0.19 mol) and formamidine acetate (22.9 g, 0.22 mol) were thenadded and the reaction mixture heated under reflux for 40 hours. Thereaction mixture was concentrated under reduced pressure, and theresidue partitioned between water (400 mL) and dichloromethane (400 mL).The aqueous phase was re-extracted with dichloromethane (2×100 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated underreduced pressure. The resulting solid was triturated with diethyl ether(100 mL) and the product collected by filtration to give the titlecompound as a light brown solid (32.0 g, 70%).

[0419]¹H-nmr (400 MHz, CDCl₃) δ: 2.64 (m, 2H), 2.73 (m, 2H), 3.48 (s,2H), 3.70 (s, 2H), 7.25-7.34 (m, 5H), 7.97 (s, 1H), 12.37 (bs, 1H).

[0420] LRMS (ES⁺): m/z 264 [MNa⁺]

Preparation 397-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0421]

[0422] The compound from preparation 38 (11.0 g, 42 mmol) was mixed withphosphorous oxychloride (80 mL) and heated to 90° C. under nitrogen gasfor 1 hour. The reaction mixture was concentrated under reducedpressure, re-dissolved in dichloromethane (100 mL) and poured onto ice(100 g). The mixture was stirred for 10 minutes, and then basified withsaturated sodium bicarbonate solution. The aqueous phase was extractedwith dichloromethane (3×150 mL) and the combined organic extracts weredried (MgSO₄) and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol (100:0 to 90:10) to give the titlecompound as a brown oil (9.75 g, 90%).

[0423]¹H-nmr (400 MHz, CDCl₃) δ: 2.81 (t, 2H), 2.85 (t, 2H), 3.68 (s,2H), 3.72 (s, 2H), 7.29-7.34 (m, 5H), 8.70 (s, 1H).

Preparation 407-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carbaldehyde

[0424]

[0425] Tellurium metal (5.72 g, 45 mmol) was suspended intetrahydrofuran (100 mL) at room temperature under nitrogen gas andn-butyl lithium (20 mL of a 2.5M solution in hexanes, 50 mmol) addedover 1 minute. This mixture was stirred for a further 15 minutes andthen added to a solution of the compound from preparation 39 (9.75 g,37.5 mmol) in tetrahydrofuran (100 mL) and the mixture stirred for 15minutes before being cooled to −78° C. n-Butyl lithium (20 mL of a 2.5Msolution in hexanes, 50 mmol) was added over 1 minute and the mixturestirred for 5 minutes before N,N-dimethylformamide (20 mL) was added.The reaction was stirred for a further 30 minutes at −78° C., quenchedwith water (10 mL) then allowed to warm to room temperature. Ethylacetate (200 mL) and water (100 mL) were added, the organic layerseparated and washed with brine (100 mL), dried (MgSO₄) and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel eluting with a solvent gradient ofdichloromethane:ethyl acetate (100:0 to 50:50) to give the titlecompound as a brown oil, 3.10 g.

[0426]¹H-nmr (400 MHz, CDCl₃) δ: 2.79 (t, 2H), 3.27 (t, 2H), 3.73 (s,2H), 3.76 (s, 2H), 7.33 (m, 5H), 9.16 (s, 1H), 10.11 (s, 1H).

[0427] LRMS (ES⁺): m/z 276 [MNa⁺]

Preparation 41 tert-Butyl5-[(cyclopropylamino)methyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0428]

[0429] Cyclopropylamine (0.81 mL, 11.4 mmol) and acetic acid (0.49 μl,0.85 mmol) were added to a solution of the aldehyde from preparation 25(2.0 g, 7.65 mmol) in tetrahydrofuran (50 mL), and the solution stirredat room temperature for 2 hours. Sodium triacetoxyborohydride (4.0-g,19.1 mmol) was added, and the reaction stirred at room temperature for72 hours. The mixture was partitioned between 0.88 ammonia (20 mL),water (25 mL) and ethyl acetate (75 mL). The layers were separated, theorganic phase washed with brine, dried (MgSO₄) and evaporated underreduced pressure to give the title compound as a clear oil, 2.34 g.

[0430]¹Hnmr (CDCl₃, 400 MHz) δ: 0.38 (m, 2H), 0.42 (m, 2H), 1.46 (s,9H), 2.16 (m, 1H), 2.84 (t, 2H), 3.65 (t, 2H), 3.80 (s, 2H), 4.58 (s,2H), 7.01 (m, 1H), 7.18 (m, 2H).

[0431] LRMS: m/z (ES⁺) 303 [MH⁺], 325 [MNa⁺]

Preparation 42 tert-Butyl5-(3-azabicyclo[3.1.0]hex-3-ylmethyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0432]

[0433] 3-Azabicyclo[3.1.0]hexane hydrochloride (WO 9522547) (203 mg, 1.7mmol) sodium acetate (140 mg, 1.7 mmol), powdered 4 Å molecular sieves(500 mg) and acetic acid (0.49 μl, 0.85 mmol) were added to a solutionof the aldehyde from preparation 25 (403 mg, 1.55 mmol) intetrahydrofuran (10 mL), and the solution stirred at room temperaturefor 1 hour. Sodium triacetoxyborohydride (720 mg, 3.4 mmol) was added,and the reaction stirred at room temperature for 18 hours. The mixturewas partitioned between sodium hydroxide solution (60 mL, 1N) and ethylacetate (60 mL) and the layers separated. The organic phase was washedwith brine (60 mL), dried (MgSO₄) and evaporated under reduced pressure.The crude product was purified by column chromatography on silica gelusing ethyl acetate: methanol (95:5) as eluant, to give a colourlessoil. This was dissolved in diethyl ether (20 mL) and the solutionextracted with 1N hydrochloric acid (2×20 mL). The combined aqueoussolutions were then basified to pH 11 using 1N sodium hydroxide solution(50 mL), and this aqueous solution extracted with ethyl acetate. Thesecombined organic extracts were dried (MgSO₄) and evaporated underreduced pressure to afford the title compound as a white solid, 224 mg.

[0434]¹H-nmr (CDCl₃, 400 MHz) δ: 0.30 (m, 1H), 0.66 (m, 1H), 1.31 (m,2H), 1.48 (s, 9H), 2.33 (d, 2H), 2.82 (m, 4H), 3.56 (s, 2H), 3.60 (t,2H), 4.57 (s, 2H), 6.99 (m, 1H), 7.09 (m, 2H).

[0435] LRMS: m/z (ES⁺) 351 [MNa⁺]

Preparation 43 tert-Butyl5-[(3-methoxy-1-azetidinyl)methyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0436]

[0437] Sodium acetate (82 mg, 1.0 mmol) the aldehyde from preparation 25(264 mg, 1.05 mmol) and acetic acid (0.07 mL, 1.2 mmol) were added to asolution of the amine hydrochloride from preparation 21 (130 mg, 1.05mmol) in tetrahydrofuran (10 mL), and the solution stirred at roomtemperature for 0.5 hour. Sodium triacetoxyborohydride (530 mg, 2.5mmol) was added, and the reaction stirred at room temperature for 18hours. The mixture was diluted with ethyl acetate and basified to pH 11using 0.88 ammonia. The layers were separated, the aqueous phaseextracted with ethyl acetate and the combined organic solutions dried(MgSO₄) and evaporated under reduced pressure. The residual yellow oilwas purified by column chromatography on silica gel usingdichloromethane:methanol (97:3) as eluant to afford the title compoundas an oil, 226 mg.

[0438]¹H-nmr (CDCl₃, 400 MHz) δ: 1.45 (s, 9H), 2.81 (t, 2H), 2.95 (t,2H), 3.22 (s, 3H), 3.60 (m, 6H), 4.01 (m, 1H), 4.58 (s, 2H), 7.00 (m,1H), 7.13 (m, 2H).

[0439] LRMS: m/z (ES⁺) 333.3 [MH⁺]

Preparation 44 tert-Butyl5-[(4-methyl-1-piperazinyl)methyl]-1-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0440]

[0441] Acetic acid (0.078 mL, 1.3 mmol) followed by sodiumtriacetoxyborohydride (572 mg, 2.7 mmol) were added to a solution of1-methylpiperazine (0.139 mL, 1.25 mmol) and the aldehyde frompreparation 25 (250 mg, 0.96 mmol) in tetrahydrofuran (10 mL), and thesolution stirred at room temperature for 3 hours. The reaction waspoured into 2N sodium hydroxide solution (50 mL), and the mixtureextracted with ethyl acetate (3×). The combined organic extracts werewashed with brine, dried (MgSO₄) and evaporated under reduced pressure.The crude product was purified by column chromatography on silica gelusing dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant toafford the title compound, 201 mg.

[0442]¹H-nmr (CDCl₃, 400 MHz) δ: 1.46 (s, 9H), 1.75 (m, 2H), 2.25 (s,3H), 2.42 (m, 6H), 2.90 (t, 2H), 3.43 (s, 2H), 3.63 (t, 2H), 4.55 (s,2H), 7.01 (m, 1H), 7.14 (m, 2H).

[0443] LRMS: m/z (ES⁺) 346 [MH⁺]

Preparation 45 tert-Butyl5-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0444]

[0445] A solution of morpholine (1.34 mL, 15.3 mmol) and the aldehydefrom preparation 25 (2.0 g, 7.65 mmol) in acetonitrile (40 mL) wasstirred at room temperature for 1.5 hours, then cooled in an ice-bath.Sodium triacetoxyborohdride (1.95 g, 9.18 mmol) was added portionwise,the reaction allowed to warm to room temperature and stirred for 6hours. The reaction was diluted with water (30 mL), extracted with ethylacetate (3×50 mL) and the combined organic extracts dried (MgSO₄) andevaporated under reduced pressure to give a yellow oil, 2.60 g.

[0446] This was purified by column chromatography on silica gel usingdichloromethane:diethyl ether (90:10 to 80:20) to afford the titlecompound as a colourless oil, 2.09 g.

[0447]¹H-nmr (CDCl₃, 400 MHz) δ: 1.47 (s, 9H), 2.39 (m, 4H), 2.90 (m,2H), 3.40 (s, 2H), 3.62 (m, 6H), 4.57 (s, 2H), 7.00 (m, 1H), 7.10 (m,2H).

[0448] LRMS: m/z (ES⁺) 355 [MNa⁺]

Preparation 46 tert-Butyl5-{[cyclopropyl(methyl)amino]methyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0449]

[0450] A mixture of the amine from preparation 41 (1.1 g, 3.43 mmol),37% aqueous formaldehyde (1.05 mL, 10.9 mmol) and sodiumtriacetoxyborohydride (3.1 g, 14.64 mmol) in dichloromethane (50 mL) wasstirred at room temperature for 18 hours. The reaction mixture waspartitioned between 0.88 ammonia (15 mL), water (30 mL) anddichloromethane (40 mL), and the layers separated. The organic phase waswashed with brine, dried (MgSO₄) and evaporated under reduced pressureto afford the title compound as a clear oil, 940 mg.

[0451]¹H-nmr (CDCl₃, 400 MHz) δ: 0.37 (m, 2H), 0.43 (m, 2H), 1.46 (s,9H), 1.69 (m, 1H), 2.20 (s, 3H), 2.86 (m, 2H), 3.60 (m, 4H), 4.53 (s,2H), 7.00 (m, 1H), 7.10 (m, 2H).

[0452] LRMS: m/z (ES⁺) 317 [MH⁺], 339 [MNa⁺]

Preparation 47 tert-Butyl5-[(1-methyl-4-piperidinyl)oxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0453]

[0454] A solution of diethylazodicarboxylate (505 mg, 2.9 mmol) indichloromethane (3 mL) was added dropwise to a cooled (4° C.) solutionof the tetrahydroisoquinolinol from preparation 22 (498 mg, 2 mmol) andtriphenylphosphine (787 mg, 3 mmol) in dichloromethane (25 mL) and thesolution stirred at this temperature for 30 minutes.1-Methyl-4-hydroxypiperidine (403 mg, 3.5 mmol) was added and thereaction stirred at room temperature for 17 hours. An additionalsolution of triphenylphosphine (393 mg, 1.5 mmol) anddiethylazodicarboxylate (226 mg, 1.3 mmol) in dichloromethane (2 mL),followed by 1-methyl-4-hydroxypiperidine (207 mg, 1.8 mmol) were addedand the reaction stirred for a further 17 hours at room temperature. Themixture was diluted with dichloromethane (50 mL), washed with water(2×75 mL), dried (MgSO₄) and concentrated under reduced pressure. Theresidual orange oil was purified by column chromatography on silica gelusing an elution gradient of dichloromethane:methanol:0.88 ammonia(97:3:0.2 to 93:7:0.7) to give the title compound as a yellow oil, 466mg.

[0455]¹Hnmr (CDCl₃, 400 MHz) δ: 1.48 (s, 9H), 1.86 (m, 2H), 1.97 (m,2H), 2.29 (s, 3H), 2.32 (m, 2H), 2.61 (m, 2H), 2.77 (t, 2H), 3.63 (t,2H), 4.34 (m, 1H), 4.54 (s, 2H), 6.69 (d, 2H), 7.09 (dd, 1H). LRMS: m/z(ES⁺) 347 [MH⁺]

Preparations 48 to 50

[0456]

[0457] Acetic acid (2.5-3.5 eq) followed by the appropriate amine(1.1-1.7 eq) were added to a solution of the aldehyde from preparation29 (1 eq) in tetrahydrofuran (5 mL per mmol) and the solution stirredfor 15 minutes. Sodium triacetoxyborohydride (2-2.3 eq.) was added, andthe reaction stirred at room temperature for 17 hours. 2N hydrochloricacid was added, to give a pH of 1, the mixture stirred for 15 minutes,then re-basified to pH 12 using 2N sodium hydroxide solution. Themixture was extracted with dichloromethane, the combined organicextracts dried (MgSO₄) and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel using anelution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5 to90:10:1) to afford the desired compound. Prep R Yield % Data 48

76 yellow gum ¹H-nmr(CDCl₃, 400MHz) δ: 2.25(s, 6H), 2.83(t, 2H), 3.01(t,2H), 3.54(s, 2H), 3.60(s, 2H), 3.70(s, 2H), 7.15(d, 1H), 7.23(m, 2H),7.35(m, 4H). LRMS: m/z(ES⁺) 304[MNa⁺] 49

86 yellow oil ¹H-nmr(CDCl₃, 400MHz) δ: 1.77(m, 4H), 2.55(m, 4H), 2.83(t,2H), 3.03(t, 2H), 3.59(s, 2H), 3.69(s, 2H), 3.72(s, 2H), 7.14-7.38(m,7H). LRMS: m/z (ES⁺) 308[MH⁺] 50

73 yellow oil ¹H-nmr(CDCl₃, 400MHz) δ: 2.49(m, 4H), 2.84(t, 2H), 3.03(t,2H), 3.59(m, 4H), 3.70(m, 6H), 7.16-7.38(m, 7H). LRMS m/z(ES⁺) 346[MNa⁺]

Preparation 512-(3-Azabicyclo[3.1.0]hex-3-ylmethyl)-6-benzyl-5,6,7,8-tetrahydro[1,6]naphthyridine

[0458]

[0459] 3-Azabicyclo[3.1.0]hexane hydrochloride (WO 9522547) (300 mg,2.49 mmol), sodium acetate (223 mg, 2.71 mmol) and acetic acid (0.8 mL)were added to a solution of the aldehyde from preparation 29 (570 mg,2.26 mmol) in tetrahydrofuran (15 mL) and dichloromethane (10 mL), andthe solution stirred at room temperature for 0.5 hour. Sodiumtriacetoxyborohydride (960 mg, 4.52 mmol) was added, and the reactionstirred at room temperature for 18 hours. The mixture was partitionedbetween sodium hydroxide solution (60 mL, 1N) and ethyl acetate (60 mL)and the layers separated. The organic phase was washed with brine (60mL), dried (MgSO₄) and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant, to give thetitle compound as a yellow oil, 375 mg.

[0460]¹H-nmr (DMSOd₆, 400 MHz) δ: 0.30 (m, 1H), 0.62 (m, 1H), 1.35 (m,2H), 2.35 (m, 2H), 2.76 (m, 2H), 2.88 (m, 4H), 3.52 (s, 2H), 3.57 (s,2H), 3.64 (s, 2H), 7.03 (d, 1H), 7.30 (m, 6H).

[0461] LRMS: m/z (ES⁺) 320 [MH⁺]

Preparation 52(1S,4S)-5-[(6-Benzyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2-yl)methyl]-2-oxa-5-azabicyclo[2.2.1]heptane

[0462]

[0463] A mixture of the aldehyde from preparation 29 (866 mg, 3.44mmol), 1S,4S-2-aza-5-oxabicyclo[2.2.1]heptane hydrochloride (700 mg,5.16 mmol), sodium acetate (423 mg, 5.16 mmol) and acetic acid (310 mg,5.16 mmol) in tetrahydrofuran (20 mL) was stirred at room temperaturefor 2 hours. 2M Hydrochloric acid (20 mL) was added cautiously, themixture stirred for 10 minutes, then the mixture basified using 1Nsodium hydroxide solution. The mixture was extracted withdichloromethane (3×60 mL), the combined organic solutions dried (MgSO₄)and evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel using an elution gradient ofdichloromethane:methanol (100:0 to 90:10) to afford the title compoundas a yellow oil, 783 mg.

[0464]¹H-nmr (CDCl₃, 400 MHz) δ: 1.79 (m, 1H), 1.99 (m, 1H), 2.69 (m,1H), 2.86 (t, 2H), 2.93 (m, 1H), 3.03 (t, 2H), 3.52 (m, 1H), 3.62 (s,2H), 3.66 (m, 1H), 3.72 (s, 2H), 3.89 (m, 2H), 4.16 (m, 1H), 4.44 (m,1H), 7.21-7.83 (m, 7H).

[0465] LRMS: m/z (APCl⁺) 336 [MH⁺]

Preparation 536-Benzyl-2-[(4-methoxy-1-piperidinyl)methyl]-5,6,7,8-tetrahydro[1,6]naphthyridine

[0466]

[0467] Triethylamine (0.43 mL, 3.2 mmol) followed by the aldehyde frompreparation 29 (750 mg, 3.0 mmol) was added to a solution of thepiperidine hydrochloride from preparation 94 (483 mg, 3.2 mmol) intetrahydrofuran (20 mL), and the solution stirred for 1 hour. Sodiumtriacetoxyborohydride (745 mg, 3.5 mmol) was added portionwise, and thereaction stirred at room temperature for 18 hours. 2N Hydrochloric acid(4 mL) was added, the solution stirred for 5 minutes, then poured intowater (80 mL), and the pH adjusted to 9 using 2N sodium hydroxidesolution. The mixture was extracted with dichloromethane (3×100 mL), thecombined organic extracts dried (MgSO₄) and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) toafford the title compound as an oil, that crystallised on standing, 710mg.

[0468]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.40 (m, 2H), 1.80 (m, 2H), 2.10 (m,2H), 2.62 (m, 2H), 2.76 (m, 2H), 2.82 (m, 2H), 3.16 (m, 1H), 3.20 (s,3H), 3.46 (s, 2H), 3.54 (s, 22H), 3.64 (s, 2H), 7.16 (2xs, 2H),7.20-7.40 (m, 5H).

[0469] LRMS: m/z (ES⁺) 352 [MH⁺]

Preparation 54N-(6-Benzyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2-yl)-N-methylamine

[0470]

[0471] Liquid methylamine (20 mL) was added to a cooled (−70° C.)solution of 6-benzyl-2-chloro-5,6,7,8-tetrahydro[1,6]naphthyridine (WO9830560) (5.5 g, 21.25 mmol) in methanol (30 mL). The mixture was heatedto 140° C. in a sealed vessel for 72 hours, then cooled. The reactionmixture was evaporated under reduced pressure and the residual brown oilpurified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol:0.88 ammonia (97:3:0 to 96:4:0.5)to afford the title compound as a white solid, 2.97 g

[0472]¹H-nmr (CDCl₃, 400 MHz) δ: 2.80 (m, 4H), 2.87 (s, 3H), 3.49 (s,2H), 3.68 (s, 2H), 4.36 (bs, 1H), 6.19 (d, 1H), 7.05 (d, 1H), 7.24 (m,1H), 7.31 (m, 2H), 7.36 (m, 2H).

[0473] LRMS: m/z (ES⁺) 254 [MH⁺]

Preparation 556-Benzyl-2-(4-morpholinyl)-5,6,7,8-tetrahydro[1,6]naphthyridine

[0474]

[0475] Morpholine (0.33 mL, 3.7 mmol), sodium tert-butoxide (337 mg, 3.7mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (124 mg, 0.2mmol) and tris(dibenzylideneacetone)dipalladium (0) (92 mg, 0.1 mmol)were added sequentially to a solution of the bromide from preparation 28(763 mg, 2.5 mmol) in toluene (10 mL), and the solution purged withnitrogen. The reaction was then stirred at 100° C. for 18 hours, cooledand filtered through silica gel, washing through with a solution ofdichloromethane:methanol. The filtrate was concentrated under reducedpressure and the residue purified by column chromatography on silica gelusing an elution gradient of dichloromethane:methanol (98:2 to 95:5) toafford the title compound.

[0476]¹H-nmr (CDCl₃, 400 MHz) δ: 2.79 (m, 2H), 2.81 (m, 2H), 3.41 (m,4H), 3.46 (s, 2H), 3.67 (s, 2H), 3.78 (m, 4H), 6.41 (d, 1H), 7.12 (s,1H), 7.30 (m, 5H).

[0477] LRMS: m/z (ES⁺) 310 [MH⁺]

Preparation 566-Benzyl-2-(4-methyl-1-piperazinyl)-5,6,7,8-tetrahydro[1,6]naphthyridine

[0478]

[0479] The title compound was obtained in 36% yield, from the bromidefrom preparation 28 and 1-methylpiperazine, following the proceduredescribed in preparation 55.

[0480]¹H-nmr (CDCl₃, 400 MHz) δ: 2.30 (s, 3H), 2.49 (m, 4H), 2.79 (m,2H), 2.82 (m, 2H), 3.49 (m, 6H), 3.08 (s, 2H), 6.42 (d, 1H), 7.09 (d,1H), 7.35 (m, 5H).

[0481] LRMS: m/z (ES⁺) 345 [MNa⁺]

Preparation 57N-[(6-Benzyl-5,6,7,8-tetrahydro[2,6]naphthyridin-1-yl)methil]-N-methyl-2-propanamine

[0482]

[0483] N-Isopropyl-N-methylamine (330 μl, 3.15 mmol) followed by aceticacid (132 μl, 2.31 mmol) were added to a solution of the aldehyde frompreparation 35 (530 mg, 2.1 mmol) in tetrahydrofuran (15 mL), and thesolution stirred at room temperature for 1 hour. Sodiumtriacetoxyborohydride (1.11 g, 5.26 mmol) was then added, and thereaction stirred for 18 hours. The reaction mixture was partitionedbetween 1N sodium hydroxide solution (30 mL), and ethyl acetate (30 mL)and the layers separated. The aqueous phase was extracted with ethylacetate (30 mL) and the combined organic extracts were dried (MgSO₄),and evaporated under reduced pressure to give an oil. This was purifiedby column chromatography on silica gel using an elution gradient ofdichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to afford thetitle compound as a yellow oil, 272 mg.

[0484]¹H-nmr (CDCl₃, 400 MHz) δ: 1.06 (d, 6H), 2.13 (s, 3H), 2.77 (t,2H), 2.85 (m, 1H), 2.99 (t, 2H), 3.58 (s, 2H), 3.62 (s, 2H), 3.66 (s,2H), 6.78 (m, 1H), 7.35 (m, 5H), 8.23 (m, 1H).

[0485] LRMS: m/z (ES⁺) 310 [MH⁺]

Preparation 582-Benzyl-5-(4-morpholinylmethyl)-1,2,3,4-tetrahydro[2,6]naphthyridine

[0486]

[0487] The title compound was obtained as a yellow oil, from thealdehyde from preparation 35 and morpholine, following a similarprocedure to that described in preparation 57.

[0488]¹H-nmr (CDCl₃, 400 MHz) δ: 2.42 (m, 4H), 2.79 (m, 2H), 2.99 (m,2H), 3.57-3.78 (m, 10H), 6.80 (d, 1H), 7.20-7.39 (m, 5H), 8.22 (d, 1H).

[0489] LRMS m/z (ES⁺) 346 [MNa⁺]

Preparation 59(6-Benzyl-5,6,7,8-tetrahydro[2,6]naphthyridin-1-yl)-N,N-dimethylmethanamine

[0490]

[0491] Dimethylamine (2 mL, 2M in tetrahydrofuran, 4 mmol) followed byacetic acid (480 mg, 8 mmol) were added to a solution of the aldehydefrom preparation 35 (756 mg, 3 mmol) in tetrahydrofuran (15 mL), and thesolution stirred at room temperature for 10 minutes. Sodiumtriacetoxyborohydride (1.27 g, 6 mmol) was then added, and the reactionstirred for 3 hours. The reaction was quenched by the addition of 2Nhydrochloric acid, this solution stirred for 15 minutes, basified using1N sodium hydroxide solution, then extracted with dichloromethane (3×50mL). The combined organic extracts were dried (MgSO₄), and evaporatedunder reduced pressure to afford the title compound as an oil, 942 mg.

[0492]¹H-nmr (CDCl₃, 400 MHz) δ: 2.23 (s, 6H), 2.79 (m, 2H), 2.98 (m,2H), 3.50 (s, 2H), 3.59 (s, 2H), 3.64 (s, 2H), 6.80 (d, 1H), 7.21-7.39(m, 5H), 8.25 (d, 1H).

Preparation 602-Benzyl-5-(1-pyrrolidinylmethyl)-1,2,3,4-tetrahydro[2,6]naphthyridine

[0493]

[0494] The title compound was obtained in 73% yield from the aldehydefrom preparation 35 and pyrrolidine, following a similar proceduredescribed in preparation 59, except the reaction was worked up usingethyl acetate and 0.88 ammonia.

[0495] 1H-nmr (CDCl₃, 400 MHz) δ: 1.76 (m, 4H), 2.55 (m, 4H), 2.78 (m,2H), 2.97 (m, 2H), 3.58 (s, 2H), 3.67 (s, 2H), 3.70 (s, 2H), 6.79 (d,1H), 7.30 (m, 5H), 8.26 (d, 1H).

[0496] LRMS: m/z (ES⁺) 308 [MH⁺]

Preparation 612-Benzyl-5-(1-piperidinylmethyl)-1,2,3,4-tetrahydro[2,6]naphthyridine

[0497]

[0498] The title compound was obtained in 68% yield from the aldehydefrom preparation 35 and piperidine, following a similar procedure tothat described in preparation 60.

[0499]¹H-nmr (CDCl₃, 400 MHz) δ: 1.40 (m, 2H), 1.50 (m, 4H), 2.40 (m,4H), 2.77 (m, 2H), 3.00 (m, 2H), 3.52 (s, 2H), 3.59 (s, 2H), 3.67 (s,2H), 6.79 (d, 2H), 7.25-7.38 (m, 5H), 8.24 (d, 1H).

[0500] HRMS: m/z (ES⁺) 322.2283 [MH⁺] C₂₁H₂₇N₃-322.2278 [MH⁺]

Preparation 622-Benzyl-5-[(4-methoxy-1-piperidinyl)methyl]-1,2,3,4-tetrahydro[2,6]naphthyridine

[0501]

[0502] The title compound was obtained as an orange oil from thealdehyde from preparation 35 and 4-methoxypiperidine hydrochloride frompreparation 94, following a similar procedure to that described inpreparation 60.

[0503]¹H-nmr (CDCl₃, 400 MHz) δ: 1.58 (m, 2H), 1.85 (m, 2H), 2.22 (m,2H), 2.77 (m, 4H), 2.99 (m, 2H), 3.19 (m, 1H), 3.32 (s, 3H), 3.60 (m,4H), 3.69 (s, 2H), 6.80 (d, 1H), 7.20-7.40 (m, 5H), 8.22 (d, 1H).

[0504] LRMS: m/z (ES⁺) 352 [MH⁺].

Preparation 63(1S,4S)-5-[(6-benzyl-5,6,7,8-tetrahydro[2,6]naphthyridin-1-yl)methyl]-2-oxa-5-azabicyclo[2.2.1]heptane

[0505]

[0506] (1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane hydrochloride (344 mg,2.54 mmol), followed by sodium acetate (152 mg, 1.86 mmol) and aceticacid (0.1 mL, 1.86 mmol) were added to a solution of the aldehyde frompreparation 35 (427 mg, 1.69 mmol) in tetrahydrofuran (15 mL), and thesolution stirred at room temperature for 1 hour. Sodiumtriacetoxyborohydride (897 mg, 4.23 mmol) was added and the reactionstirred at room temperature for 18 hours. The mixture was concentratedunder reduced pressure and the residue partitioned between ethyl acetate(50 mL) and 0.88 ammonia (50 mL), the layers separated, and the aqueousphase further extracted with ethyl acetate (50 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated under reduced pressure.The crude product was purified by column chromatography on silica gelusing an elution gradient of dichloromethane:methanol (98:2 to 95:5) toafford the title compound as a yellow oil, 324 mg.

[0507]¹H-nmr (CDCl₃, 400 MHz) δ: 1.68 (d, 1H), 1.88 (d, 1H), 2.65 (d,1H), 2.78 (m, 2H), 2.89 (d, 1H), 2.97 (m, 2H), 3.40 (s, 1H), 3.59 (s,2H), 3.65 (m, 3H), 3.80 (dd, 2H), 4.06 (d, 1H), 4.38 (s, 1H), 6.79 (d,1H), 7.30 (m, 5H), 8.22 (d, 1H).

[0508] LRMS: m/z (ES⁺) 358 [MNa⁺]

Preparation 645-(7-Azabicyclo[2.2.1]hept-7-ylmethyl)-2-benzyl-1,2,3,4-tetrahydro[2,6]naphthyridine

[0509]

[0510] Diisopropylethylamine (720 μl, 4.13 mmol) was added to a solutionof 7-azabicyclo[2.2.1]heptane (Can. J. Chem. 1970; 48(13); 2065) (500mg, 3.75 mmol) in dichloromethane (7 mL), and the solution stirred for40 minutes. A solution of the aldehyde from preparation 35 (650 mg, 2.57mmol) in dichloromethane (2 mL) was added, followed by acetic acid (300μl, 5.16 mmol), and the solution stirred for a further 2 hours. Sodiumtriacetoxyborohydride (1.1 g, 5.16 mmol) was added, and the reactionstirred at room temperature for 18 hours. The mixture was quenched bythe addition of 2N hydrochloric acid (3 mL), then basified using 1Nsodium hydroxide solution (20 mL). The mixture was extracted withdichloromethane (2×), the combined organic extracts dried (Na₂SO₄) andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel using an elution gradient ofdichloromethane:methanol:0.88 ammonia (100:0:0 to 94:5:1) to afford thetitle compound as a brown oil.

[0511]¹H-nmr (CDCl₃, 400 MHz) δ: 1.25 (m, 4H), 1.80 (m, 4H), 2.78 (t,2H), 3.05 (t, 2H), 3.25 (m, 2H), 3.58 (s, 2H), 3.61 (m, 2H), 3.67 (s,2H), 6.79 (d, 1H), 7.30 (m, 5H), 8.22 (d, 1H).

[0512] LRMS: m/z (ES⁺) 334 [MH⁺]

Preparation 65 tert-Butyl4-(6-benzyl-5,6,7,8-tetrahydro[2,6]naphthyridin-1-yl)-1-piperidinecarboxylate

[0513]

[0514] Zinc (809 mg, 12.4 mmol) was stirred in 1N hydrochloric acid (5mL) for 5 minutes, the mixture filtered, and the collected zinc washedwith water, ethanol and diethyl ether, then dried at 100° C. for 5hours.

[0515] Dibromoethane (28 μl, 0.33 mmol) was added to a suspension of thezinc in N,N-dimethylformamide (12 mL), and the mixture heated at 50° C.for 4 minutes, then cooled. Trimethylsilyl chloride (54 mg, 0.50 mmol)was added, the mixture again heated at 50° C. for 5 minutes, tert-butyl4-iodo-1-piperidinecarboxylate (EP 1078928) (2.57 g, 8.25 mmol) addedand stirring continued for 5 minutes. A solution of the bromide frompreparation 34 (1.0 g, 3.3 mmol) in N,N-dimethylformamide (2.5 mL),tris(dibenzylideneacetone)dipalladium (0) (38 mg, 0.07 mmol) andtri(o-furyl)phosphine (31 mg, 0.13 mmol) were added, and the reactionmixture heated at 60° C. for 1 hour. The cooled mixture was partitionedbetween dichloromethane (50 mL) and water (20 mL), and the phasesseparated. The aqueous layer was extracted with further dichloromethane(2×50 mL), and the combined organic extracts were dried (MgSO₄),filtered through Arbocel® and evaporated under reduced pressure. Theresidual orange oil was purified by column chromatography on silica gelusing an elution gradient of dichloromethane:methanol (100:0 to 96:4) togive the title compound, as an oil, 1.0 g.

[0516]¹H-nmr (CDCl₃, 400 MHz) δ: 1.45 (s, 9H), 1.65 (m, 2H), 1.85 (m,4H), 2.78 (m, 4H), 2.86 (m, 2H), 3.02 (m, 1H), 3.58 (s, 2H), 3.67 (s,2H), 6.74 (d, 1H), 7.24-7.37 (m, 5H), 8.25 (d, 1H).

[0517] LRMS: m/z (ES⁺) 408 [MH⁺]

Preparation 662-Benzyl-5-(4-piperidinyl)-1,2,3,4-tetrahydro[2,6]naphthyridinetrihydrochloride

[0518]

[0519] A solution of the protected amine from preparation 65 (990 mg,2.43 mmol) in dry dichloromethane (30 mL) was cooled in an ice/acetonebath and hydrogen chloride gas bubbled through, until saturation. Thesolution was stirred for a further 2 hours, then evaporated underreduced pressure to afford the title compound as a cream foam, 924 mg.

[0520]¹H-nmr (CD₃OD, 400 MHz) δ: 1.74 (m, 1H), 2.00 (m, 1H), 2.20 (m,4H), 3.09 (m, 1H), 3.29 (m, 2H), 3.45 (m, 2H), 3.56 (m, 2H), 4.60 (s,2H), 4.67 (s, 2H), 7.53 (m, 3H), 7.68 (m, 3H), 8.58 (d, 1H).

[0521] LRMS: m/z (ES⁺) 308 [MH⁺]

Preparation 672-Benzyl-5-(1-methyl-4-piperidinyl)-1,2,3,4-tetrahydro[2,6]naphthyridine

[0522]

[0523] Triethylamine (675 μl, 4.81 mmol) was added to a solution of theamine from preparation 66 (914 mg, 2.40 mmol) in acetonitrile (10 mL),followed by dropwise addition of formaldehyde (37% aq., 390 mg, 4.81mmol), and the solution stirred at room temperature for 1 hour. Sodiumtriacetoxyborohydride (2.546 g, 12.02 mmol) was added portionwise andthe reaction stirred at room temperature for 72 hours. The mixture wasdiluted with water (10 mL), then neutralised using sodium bicarbonatesolution and extracted with 5% methanol in dichloromethane solution(3×30 mL). The combined organic extracts were evaporated under reducedpressure and the residual orange oil, purified by column chromatographyon silica gel using an elution gradient of dichloromethane:methanol:0.88ammonia (96:4:0 to 90:10:0.5) to give the title compound as an orangeoil, 690 mg.

[0524]¹H-nmr (CDCl₃, 400 MHz) δ: 1.77 (m, 2H), 2.07 (m, 4H), 2.33 (s,3H), 2.77 (m, 3H), 2.84 (t, 2H), 3.01 (m, 2H), 3.57 (s, 2H), 3.67 (s,2H), 6.72 (d, 1H), 7.25-7.35 (m, 5H), 8.27 (d, 1H).

[0525] LRMS: m/z (ES⁺) 322 [MH⁺]

Preparation 68 N,6-Dibenzyl-5,6,7,8-tetrahydro[2,6]naphthyridin-1-amine

[0526]

[0527] A mixture of the bromide from preparation 34 (303 mg, 1 mmol) andbenzylamine (3 mL) was stirred at 160° C. for 12 hours. The cooledmixture was poured into ethyl acetate, washed with water, then dried(MgSO₄) and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel using an elution gradient ofdichloromethane:ethyl acetate (100:0 to 60:40) to afford the titlecompound as a pale yellow oil, 249 mg.

[0528]¹H-nmr (CDCl₃, 400 MHz) δ: 2.42 (t, 2H), 2.80 (t, 2H), 3.54 (s,2H), 3.66 (s, 2H), 4.26 (m, 1H), 4.67 (d, 2H), 6.29 (d, 1H), 7.20-7.40(m, 10H), 7.94 (d, 1H).

[0529] LRMS: m/z (ES⁺) 330 [MH⁺]

Preparation 69 tert-Butyl2-(2-pyrrolidinylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0530]

[0531] Triethylamine (0.36 mL, 2.6 mmol), followed by methanesulphonylchloride (0.22 mL, 2.9 mmol) were added to an ice-cold solution of thealcohol from preparation 37 (600 mg, 2.4 mmol) in dichloromethane (6mL), and the solution stirred at room temperature for 3 hours. Themixture was evaporated under reduced pressure, and the residuere-dissolved in tetrahydrofuran (6 mL). Pyrrolidine (0.99 mL, 11.9 mmol)was added, and the reaction stirred at room temperature for 18 hours.The mixture was partitioned between dichloromethane (50 mL) and water(50 mL), the layers separated and the organic phase dried (MgSO₄) andevaporated under reduced pressure. The residual yellow oil was purifiedby column chromatography using an elution gradient ofdichloromethane:methanol:0.88 ammonia (98:2:0.2 to 95:5:0.5) to affordthe title compound, 600 mg.

[0532]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.49 (s, 9H), 1.81 (m, 4H), 2.65 (m,4H), 2.95 (t, 2H), 3.73 (t, 2H), 3.87 (s, 2H), 4,56 (s, 2H), 8.42 (s,1H).

[0533] LRMS: m/z (ES⁺) 319 [MH⁺]

Preparation 70 tert-Butyl2-{[(2-methoxnethyl)(methyl)amino]methyl}-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0534]

[0535] Diisopropylethylamine (388 mg, 3 mmol) was added to an ice-coldsolution of the alcohol from preparation 37 (530 mg, 2 mmol) indichloromethane (10 mL). Methanesulphonyl chloride (267 mg, 2.33 mmol)was added, and the reaction stirred at room temperature for 1 hour.2-Methoxyethylmethylamine (890 mg, 10 mmol) was added and the reactionstirred at room temperature for a further 18 hours. The mixture waspoured into water, then extracted with dichloromethane (3×40 mL), thecombined organic extracts dried (MgSO₄) and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel using an elution gradient of dichloromethane:methanol (100:0to 97:3) to afford the title compound as a yellow oil, 285 mg.

[0536]¹H-nmr (CDCl₃, 400 MHz) δ: 1.49 (s, 9H), 2,40 (s, 3H), 2,75 (t,2H), 2,95 (t, 2H), 3.34 (s, 3H), 3.58 (t, 2H), 3.76 (t, 2H), 3.83 (s,2H), 4.59 (s, 2H), 8.42 (s, 1H).

[0537] LRMS: m/z (ES⁺) 359 [MNa⁺]

Preparation 71 tert-Butyl2-[(dimethylamino)methyl]-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0538]

[0539] The title compound was obtained as an orange oil, from thealcohol from preparation 37 and dimethylamine (2M in tetrahydrofuran),using a similar procedure to that described in preparation 70.

[0540]¹H-nmr (CDCl₃, 400 MHz) δ: 1.49 (s, 9H), 2.38 (s, 6H), 2.98 (t,2H), 3.66 (s, 2H), 3.74 (t, 2H), 4.58 (s, 2H), 8.44 (s, 1H).

[0541] LRMS: m/z (ES⁺) 315 [MNa⁺]

Preparation 72 tert-Butyl2-(1-piperidinlmethyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0542]

[0543] The title compound was obtained as a yellow oil in 54% yield fromthe alcohol from preparation 37 and piperidine, using a similar methodto that described in preparation 70.

[0544]¹H-nmr (CDCl₃, 400 MHz) δ: 1.44 (m, 11H), 1.60 (m, 4H), 2.45 (m,4H), 2.97 (t, 2H), 3.74 (m, 4H), 4.58 (s, 2H), 8.44 (s, 1H).

[0545] LRMS: m/z (ES⁺) 355 [MNa⁺]

Preparation 73 tert-Butyl2-{[2-(4-morpholinyl)ethoxy]methyl}-7,8-dihydropyrido[4.3-d]pyrimidine-6(5H)-carboxylate

[0546]

[0547] Triethylamine (305 μl, 2.19 mmol) and methanesulphonyl chloride(185 μl, 2.39 mmol) were added to an ice-cold solution of the alcoholfrom preparation 37 (500 mg, 1.99 mmol) in dichloromethane (5 mL), andthe solution stirred at room temperature for 2 hours.

[0548] 4-(2-Hydroxyethyl)morpholine (730 μl, 5.98 mmol) was addeddropwise to an ice-cooled suspension of sodium hydride (265 mg, 60%dispersion in mineral oil, 6.57 mmol) in tetrahydrofuran (5 mL), andonce addition was complete, the mixture was stirred at room temperaturefor 1.5 hours.

[0549] The first solution was concentrated under reduced pressure, theresidual yellow oil redissolved in tetrahydrofuran (2 mL), and theprepared solution of 2-hydroxyethylmorpholine anion, added dropwise. Theresulting mixture was stirred at room temperature for 18 hours, thenpartitioned between water (30 mL) and dichloromethane (30 mL). Thelayers were separated, the aqueous phase extracted with furtherdichloromethane (30 mL), and the combined organic solutions dried(Na₂SO₄) and evaporated under reduced pressure. The residual brown oilwas purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (98:2:1) as eluant to afford thetitle compound as a yellow oil, 600 mg.

[0550]¹H-nmr (CDCl₃, 400 MHz) δ: 1.49 (s, 9H), 2.52 (m, 4H), 2.68 (t,2H), 2.95 (t, 2H), 3.60 (m, 2H), 3.75 (m, 6H), 4.58 (s, 2H), 4.71 (s,2H), 8.45 (s, 1H).

[0551] LRMS: m/z (ES⁺) 401 [MNa⁺]

Preparation 747-Benzyl-4-(1-pyrrolidinylmethyl)-5.6,7,8-tetrahydropyridor[3,4-d]pyrimidine

[0552]

[0553] Pyrrolidine (322 mg, 4.54 mmol) and acetic acid (420 mg, 7 mmol)were added to a solution of the aldehyde from preparation 40 (574 mg,2.27 mmol) in tetrahydrofuran (25 mL), and the solution stirred at roomtemperature for 30 minutes. Sodium triacetoxyborohydride (1.48 g, 7mmol) was added, and the reaction stirred for a further 4 hours. Themixture was basified using saturated sodium bicarbonate solution, andextracted using dichloromethane (3×50 mL). The combined organic extractswere dried (MgSO₄) and evaporated under reduced pressure. The crudeproduct was purified using column chromatography on silica gel using anelution gradient of dichloromethane:methanol (100:0 to 85:5) to affordthe title compound as a yellow oil, 401 mg.

[0554]¹H-nmr (CDCl₃, 400 MHz) δ: 1.78 (m, 4H), 2.59 (m, 4H), 2.78 (t,2H), 2.91 (t, 2H), 3.68 (s, 2H), 3.69 (s, 2H), 3.71 (s, 2H), 7.25-7.35(m, 5H), 8.87 (s, 1H).

[0555] LRMS: m/z (ES⁺) 309 [MH⁺]

Preparation 757-Benzyl-4-(1-piperidinylmethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0556]

[0557] The title compound was obtained as colourless crystals in 52%yield from the aldehyde from preparation 40 and piperidine, following asimilar procedure to that described in preparation 74.

[0558]¹H-nmr (CDCl₃, 400 MHz) δ: 1.43 (m, 2H), 1.56 (m, 4H), 2.40 (m,4H), 2.77 (t, 2H), 2.95 (t, 2H), 3.49 (s, 2H), 3.68 (s, 2H), 3.71 (s,2H), 7.35 (m, 5H), 8.86 (s, 1H).

[0559] LRMS: m/z (ES⁺) 345 [MNa⁺]

Preparation 767-Benzyl-4-[(4-methoxy-1-piperidinyl)methyl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0560]

[0561] The title compound was obtained as a yellow oil in 44% yield,from the aldehyde from preparation 40 and the amine hydrochloride frompreparation 94, following a similar procedure to that described inpreparation 74, except, 1.2 eq of diisopropylethylamine was also used inthe reaction.

[0562]¹H-nmr (CDCl₃, 400 MHz) δ: 1.56 (m, 2H), 1.88 (m, 2H), 2.22 (m,2H), 2.70 (m, 2H), 2.77 (t, 2H), 2.94 (t, 2H), 3.22 (m, 1H), 3.32 (s,3H), 3.52 (s, 2H), 3.68 (s, 2H), 3.71 (s, 2H), 7.25-7.36 (m, 5H), 8.86(s, 1H).

[0563] LRMS: m/z (ES⁺) 375 [MNa⁺]

Preparation 77 2-[Benzyl(1H-imidazol-4-ylmethyl)amino]ethanol

[0564]

[0565] A suspension of 4-imidazolecarboxaldehyde (14 g, 145.7 mmol) andN-benzylethanolamine (26.4 g, 174.8 mmol) in tetrahydrofuran (200 mL)was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride(37.06 g, 174.8 mmol) was added portionwise over 40 minutes, and thereaction stirred at room temperature for 18 hours. The reaction wasquenched by the addition of water (150 mL), the mixture neutralisedusing saturated sodium bicarbonate solution, and then extracted withdichloromethane (3×300 mL). The combined organic extracts were dried(MgSO₄) and evaporated under reduced pressure to give a yellow oil. Thiswas purified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol:0.88 ammonia (95:5:0 to 90:10:1) toafford the title compound, 18.1 g.

[0566]¹H-nmr (CDCl₃, 400 MHz) δ: 2.73 (t, 2H), 3.63 (t, 2H), 3.67 (s,2H), 3.71 (s, 2H), 6.88 (s, 1H), 7.25-7.31 (m, 5H), 7.57 (s, 1H). LRMS:m/z (ES⁻) 230 [M−H]⁻

Preparation 78N-Benzyl-N-(2-chloroethyl)-N-(1H-imidazol-4-ylmethyl)aminedihydrochloride

[0567]

[0568] Thionyl chloride (11.35 mL, 155.6 mmol) was added to a solutionof the alcohol from preparation 77 (9.0 g, 38.9 mmol) in dichloromethane(200 mL) over 20 minutes. The solution was then stirred under reflux for3 hours, and allowed to cool. The mixture was concentrated under reducedpressure and azeotroped with acetonitrile (2×) and dried in vacuo, toafford the title compound as a solid, 11.14 g.

[0569]¹H-nmr (CD₃OD, 400 MHz) δ: 3.24 (m, 2H), 3.78 (m, 2H), 4.15 (s,2H), 4.25 (s, 2H), 7.40 (m, 3H), 7.46 (m, 2H), 7.64 (s, 1H), 8.88 (s,1H). LRMS: m/z (ES⁺) 250 [MH⁺]

Preparation 79 7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

[0570]

[0571] Triethylamine (19.55 mL, 140 mmol) was added to a solution of thechloride from preparation 78 (11.12 g, 38.9 mmol) in acetonitrile (150mL) over 20 minutes, and the reaction heated under reflux for 6 hours.The cooled mixture was filtered, and the filtrate concentrated underreduced pressure. The residual oil was partitioned betweendichloromethane (300 mL) and saturated sodium bicarbonate solution (150mL) and the phases separated. The aqueous layer was extracted withfurther dichloromethane (2×300 mL), and the combined organic extractsdried (MgSO₄) and evaporated under reduced pressure. The crude productwas purified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol (100:0 to 95:5) to afford the titlecompound as an orange solid, 3.62 g.

[0572]¹H-nmr (CDCl₃, 400 MHz) δ: 2.84 (t, 2H), 3.67 (s, 2H), 3.70 (s,2H) 4.02 (t, 2H), 6,73 (s, 1H), 7.25-7.35 (m, 6H). LRMS: m/z (ES⁺) 214[MH⁺]

Preparation 80 7-Benzyl-3-ethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

[0573]

[0574] n-Butyllithium (3.3 mL, 1.6M in hexanes, 5.28 mmol) was addeddropwise to a cooled (−78° C.) solution of the compound from preparation79 (1.0 g, 4.69 mmol) in tetrahydrofuran (10 mL), so as to maintain thetemperature below −70° C., and the solution then allowed to warm to 0°C. over 30 minutes. Ethyl iodide (1.22 mL, 15.0 mmol) was added, and themixture stirred at 0° C. for 45 minutes. The reaction was allowed towarm to room temperature, then partitioned between ethyl acetate (30 mL)and saturated sodium bicarbonate solution (6 mL). The phases wereseparated, the aqueous layer extracted with further ethyl acetate, andthe combined organic extracts dried (MgSO₄) and evaporated under reducedpressure. The residual orange oil was purified by column chromatographyon silica gel using an elution gradient of dichloromethane:methanol(99:1 to 90:10) to afford the title compound as an orange oil, 552 mg.

[0575]¹H-nmr (CDCl₃, 400 MHz) δ: 1.30 (t, 3H), 2.62 (q, 2H), 2.84 (t,2H), 3.63 (s, 2H), 3.68 (s, 2H), 3.85 (t, 2H), 6.62 (s, 1H), 7.24-7.34(m, 5H).

[0576] LRMS: m/z (ES⁺) 242 [MH⁺]

Preparation 81 7-Benzyl-3-methyl-5,6,7,8-tetrahydroimidazo[15-a]pyrazine

[0577]

[0578] The title compound was obtained as an orange oil in 89% yieldfrom the compound from preparation 79 and methyl iodide, following theprocedure described in preparation 80.

[0579]¹H-nmr (CDCl₃, 400 MHz) δ: 2.30 (s, 3H), 2.84 (t, 2H), 3.62 (s,2H), 3.68 (s, 2H), 3.83 (t, 2H), 6.59 (s, 1H), 7.25-7.34 (m, 5H). LRMS:m/z (ES⁺) 228 [MH⁺].

Preparation 822-(7-Benzyl-5,6,7,8-tetrahydroimidazo[1.5-a]pyrazin-3-yl)-2-propanol

[0580]

[0581] n-Butyllithium (6.21 mL, 1.6M in hexanes, 9.94 mmol) was addeddropwise to a cooled (−78° C.) solution of the compound from preparation79 (2.0 g, 9.38 mmol) in tetrahydrofuran (20 mL), so as to maintain thetemperature below −70° C., and the solution then allowed to warm to 0°C. over 30 minutes. Acetone (2.06 mL, 28.13 mmol) was added, and themixture stirred at 0° C. for 45 minutes. The reaction was allowed towarm to room temperature, then quenched by the addition of water (10mL), then neutralised using 2N hydrochloric acid. The mixture wasextracted with ethyl acetate (3×50 mL), and the combined organicextracts dried (MgSO₄) and evaporated under reduced pressure. Theresidual orange oil was purified by column chromatography on silica gelusing an elution gradient of dichloromethane:methanol (99:1 to 94:6) toafford the title compound as a solid, 1.21 g.

[0582]¹H-nmr (CDCl₃, 400 MHz) δ: 1.63 (s, 6H), 2.80 (t, 2H), 3.63 (s,2H), 3.67 (s, 2H), 4.23 (t, 2H), 6.60 (s, 1H), 7.25-7.39 (m, 5H).

[0583] LRMS: m/z (ES⁺) 272 [MH⁺]

Preparation 83 7-Benzyl-3-bromo-5,6,7,8-tetrahydroimidazo[1.5-a]pyrazine

[0584]

[0585] n-Butyllithium (2.2 mL, 2.5M in hexane, 5.5 mmol) was addeddropwise to a cooled (−78° C.) solution of the compound from preparation79 (1.07 g, 5 mmol) in tetrahydrofuran (20 mL), and the solution stirredfor 15 minutes. Bromine (880 mg, 5.5 mmol) was then added dropwise, thereaction stirred for a further 15 minutes, then poured into water. Themixture was extracted with dichloromethane (3×50 mL), the combinedorganic extracts dried (MgSO₄) and concentrated under reduced pressure.The crude product was purified by column chromatography using an elutiongradient of dichloromethane:methanol (100:0 to 95:5), then repeatedusing dichloromethane:ethyl acetate (100:0 to 60:40), to afford thetitle compound as a pale yellow crystalline solid, 979 mg.

[0586]¹H-nmr (CDCl₃, 400 MHz) δ: 2.86 (t, 2H), 3.62 (s, 2H), 3.69 (s,2H), 3.86 (t, 2H), 6.71 (s, 1H), 7.25-7.34 (m, 5H). LRMS: m/z (ES⁺) 314,316 [MNa⁺]

Preparation 84 3-Azido-7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

[0587]

[0588] n-Butyllithium (1.23 mL, 2.5M in hexanes, 3.09 mmol) was added toa cooled (−78° C.) solution of the compound from preparation 79 (548 mg,2.57 mmol) in tetrahydrofuran (10 mL), and the mixture stirred for 10minutes. p-Toluenesulphonyl azide (WO 9824759) (609 mg, 3.09 mmol) wasadded, the reaction stirred for a further 10 minutes, and then saturatedsodium bicarbonate solution (4 mL) added. The mixture was warmed to roomtemperature, diluted with brine, and extracted with dichloromethane(2×60 mL). The combined organic solutions were dried (MgSO₄), andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using an elution gradient ofdichloromethane:ethyl acetate (100:0 to 60:40) to afford the titlecompound as a yellow-orange oil, 154 mg.

[0589]¹H-nmr (CDCl₃, 400 MHz) δ: 2.79 (t, 2H), 3.58 (s, 2H), 3.66 (s,2H), 3.70 (t, 2H), 6.56 (s, 1H), 7.25-7.36 (m, 5H).

[0590] LRMS: m/z (ES⁺) 277 [MNa⁺]

Preparation 85N-(7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-N,N-dimethylamine

[0591]

[0592] A solution of the bromide from preparation 83 (950 mg, 3.25 mmol)in ethanolic dimethylamine (33%, 12 mL) was heated at 140° C. in asealed vessel for 4 days. The cooled mixture was poured into water, andextracted with dichloromethane (3×50 mL). The combined organic extractswere dried (MgSO₄) and evaporated under reduced pressure. The residuewas purified by column chromatography on silica gel, using an elutiongradient of dichloromethane:methanol (100:0 to 95:5) and repeated usingethyl acetate:methanol (100:0 to 95:5) to afford the title compound asan orange oil, 172 mg.

[0593]¹H-nmr (CDCl₃, 400 MHz) δ: 2.75 (s, 6H), 2.79 (t, 2H), 3.60 (s,2H), 3.67 (s, 2H), 3.80 (t, 2H), 6.44 (s, 1H), 7.25-7.38 (m, H). LRMS:m/z (ES⁺) 257 [MH⁺]

Preparation 867-Benzyl-N-(2-methoxyethyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine

[0594]

[0595] A solution of the bromide from preparation 83 (52 mg, 0.18 mmol)in N-(2-methoxyethyl)methylamine (3 mL) was heated at 140° C. for 18hours in a sealed vessel. The reaction was heated to 185° C. for afurther 5 hours, then cooled and partitioned between 0.1N sodiumhydroxide solution and dichloromethane. The layers were separated, theaqueous phase extracted with further dichloromethane (2×50 mL), and thecombined organic solutions dried (MgSO₄) and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel using ethyl acetate:methanol:0.88 ammonia (100:0:0 to 93:7:0.7) toafford the title compound as a yellow oil, 75 mg.

[0596]¹H-nmr (CDCl₃, 400 MHz) δ: 2.76 (m, 5H), 3.18 (t, 2H), 3.32 (s,3H), 3.48 (t, 2H), 3.59 (s, 2H), 3.66 (s, 2H), 3.82 (t, 2H), 6.46 (s,1H), 7.25-7.36 (m, 5H).

[0597] LRMS: m/z (ES⁺) 323 [MNa⁺]

Preparation 871-(7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-1-methylethylacetate and Preparation 887-Benzyl-3-isopropenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

[0598]

[0599] Acetic anhydride (541 μl, 5.74 mmol) was added dropwise to asolution of the alcohol from preparation 82 (1.25 g, 4.59 mmol) inpyridine (20 mL), containing 4-dimethylaminopyridine (70 mg, 0.57 mmol).The solution was stirred at room temperature for 72 hours thenevaporated under reduced pressure. The residual orange oil waspartitioned between ethyl acetate (100 mL) and 10% sodium bicarbonatesolution (50 mL), and the layers separated. The organic phase was washedwith water (2×50 mL), dried (MgSO₄) and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel using an elution gradient of dichloromethane:methanol (100:0to 94:6) to afford the title compound as an orange oil, 471 mg.

[0600]¹H-nmr (CDCl₃, 400 MHz) (2:3 mixture of compounds) δ: 1.84 (s,6H), 2.02 (s, 3H), 2.19 (s, 3H), 2.80 (t, 2H), 2.80 (t, 2H), 3.65 (2xs,4H), 3.70 (2xs, 4H), 4.04 (m, 2H), 4.04 (m, 2H), 5.29 (s, 2H), 6.64 (s,1H), 6.77 (s, 1H), 7.27-7.37 (m, 5H), 7.27-7.37(m, 5H).

[0601] LRMS: m/z (ES⁺) 336 [MNa⁺] (preparation 87)

[0602] LRMS: m/z (ES⁺) 254 [MH⁺] (preparation 88)

Preparation 89 Formyl(2-oxobutyl)formamide

[0603]

[0604] A mixture of bromobutan-2-one (10 g, 66 mmol), and sodiumdiformylamide (6.8 g, 72 mmol) in acetonitrile (50 mL) was stirred atroom temperature for 3 hours, then warmed to 35° C. for 2 hours. Themixture was stirred for a further 48 hours at room temperature, thenfiltered, washing through with additional acetonitrile (50 mL). Thefiltrate was evaporated under reduced pressure to afford the titlecompound as a clear oil, 9.1 g.

[0605]¹H-nmr (CDCl₃, 400 MHz) δ: 1.10 (t, 3H), 2.50 (q, 2H), 4.42 (s,2H), 8.90 (bs, 2H).

Preparation 90 1-Amino-2-butanone hydrochloride

[0606]

[0607] A solution of the compound from preparation 89 (9.1 g, 63.6 mmol)in ethanolic hydrochloric acid (5%, 175 mL) was stirred at roomtemperature for 48 hours. The reaction was then evaporated under reducedpressure to afford the title compound as a tan-coloured solid, 6.3 g.

[0608]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.96 (t, 3H), 2.50 (q, 2H), 3.84 (bs,2H), 8.38 (bs, 3H).

[0609] LRMS: m/z (ES⁺) 175 [2M+H]⁺

Preparation 91 Benzyl 3-thioxo-1-piperazinecarboxylate

[0610]

[0611] Lawesson's reagent (10.1 g, 20 mmol) was added to a solution ofbenzyl 3-oxo-1-piperazinecarboxylate (10 g, 43 mmol) in tetrahydrofuran(110 mL), and the reaction heated under reflux for 4 hours. The cooledmixture was concentrated under reduced pressure and the residuepartitioned between 1N sodium hydroxide solution (150 mL) and ethylacetate (250 mL), and the layers separated. The organic extract waswashed with 1N sodium hydroxide solution (2×100 mL), then brine (100mL), and the combined aqueous solutions extracted with ethyl acetate(200 mL). The combined organic solutions were dried (MgSO₄) andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel using dichloromethane:methanol(98:2) as eluant to afford the title compound as a tan-coloured solid,6.7 g.

[0612]¹H-nmr (DMSOd₆, 400 MHz) δ: 3.24-3.34 (m, 2H), 3.58 (m, 2H), 4.36(s, 2H), 5.10 (s, 2H), 7.30-7.40 (m, 5H). LRMS: m/z (ES⁺) 273 [MNa⁺]

Preparation 92 Benzyl3-ethyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate

[0613]

[0614] Methyl iodide (2.18 mL, 35 mmol) was added to a solution of thecompound from preparation 91 (1 g, 3.5 mmol) in tetrahydrofuran (15 mL),and the reaction stirred at room temperature for 18 hours. The mixturewas concentrated under reduced pressure, the residue re-dissolved intetrahydrofuran (15 mL), diisopropylethylamine (1 mL) and the compoundfrom preparation 90 (500 mg, 4 mmol) added, and the solution stirred atroom temperature for 18 hours, followed by a further 2 hours underreflux. Acetic acid (15 mL) was added, the mixture concentrated underreduced pressure to a volume of about 15 mL, then heated under refluxfor 1 hour. The reaction was evaporated under reduced pressure and theresidue purified by column chromatography on silica gel usingdichloromethane:methanol (95:5) as eluant to afford the title compoundas a pale orange solid, 620 mg.

[0615]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.14 (t, 3H), 3.10 (q, 2H), 3.60 (m,2H), 3.82 (m, 2H), 4.60 (bs, 2H), 5.12 (s, 2H), 6.64 (s, 1H), 7.36 (m,5H).

[0616] LRMS: m/z (ES⁺) 286 [MH]⁺

Preparation 93 tert-Butyl 4-methoxy-1-piperidinecarboxylate

[0617]

[0618] Sodium hydride (1.19 g, 60% in mineral oil, 29.7 mmol) was addedportionwise to a cooled (10° C.) solution of tert-butyl4-hydroxy-1-piperidinecarboxylate (Bioorg. Med. Chem. Lett.10;24;2000;2815) in tetrahydrofuran (80 mL), and the suspension stirredat room temperature for 1 hour. Iodomethane (1.85 mL, 29.7 mmol) wasadded, and the reaction stirred at 50° C. for 20 hours. The mixture wasdiluted with water (50 mL), extracted with ethyl acetate (2×150 mL) andthe combined organic extracts washed with saturated sodium bicarbonatesolution (50 mL), dried (MgSO₄) and evaporated under reduced pressure,to afford the title compound as a golden oil, 5.24 g.

[0619]¹H-nmr (CDCl₃, 400 MHz) δ: 1.47 (s, 9H), 1.50 (m, 2H), 1.80 (m,2H), 3.08 (m, 2H), 3.34 (m, 4H), 3.75 (m, 2H).

[0620] LRMS: m/z (ES⁺) 238 [MNa⁺]

Preparation 94 4-Methoxypiperidine hydrochloride

[0621]

[0622] Hydrogen chloride was bubbled through an ice-cooled solution ofthe compound from preparation 93 (5.2 g, 24.2 mmol) in dichloromethane(100 mL), and the reaction stirred for 1.5 hours. The solution waspurged with nitrogen, then evaporated under reduced pressure to affordthe title compound as an off-white solid, 3.67 g.

[0623]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.87 (m, 2H), 1.99 (m, 2H), 3.10 (m,2H), 3.28 (m, 2H), 3.36 (s, 3H), 3.54 (m, 1H).

[0624] LRMS: m/z (ES⁺) 231 [2MH⁺]

Preparation 95N-(1,2,3,4-Tetrahydro-5-isoquinolinylmethyl)cyclopropanaminedihydrochloride

[0625]

[0626] Hydrogen chloride was bubbled through an ice-cooled solution ofthe protected amine from preparation 29 (1.17 g, 3.87 mmol) indichloromethane (35 mL), for 20 minutes. The reaction was then stirredfor a further 30 minutes at room temperature and evaporated underreduced pressure to afford the title compound as a white solid, 1.15 g.

[0627]¹Hnmr (DMSOd₆, 400 MHz) δ: 0.83 (m, 2H), 0.95 (m, 2H), 2.67 (m,1H), 3.10 (t, 2H), 3.34 (m, 2H), 4.17 (s, 2H), 4.26 (s, 2H), 7.26 (m,2H), 7.48 (d, 1H), 9.60 (bs, 4H).

[0628] LRMS: m/z (ES⁺) 203 [MH⁺]

Preparations 96 to 99

[0629] The following compounds of general structure:

[0630] were prepared from the corresponding protected amines, followingthe procedure described in preparation 95: Prep no R Form Data 96

White solid ¹Hnmr(DMSOd₆, 400MHz) (rotamers) δ: 0.70(m, 4H), 1.15(m,1H), 2.67(2xs, 3H), 2.90(m, 1H), 3.33(m, 2H), 4.20(s, 2H), 4.40(2xs,2H), 7.30(m, 2H), 7.60(m, 1H), 9.63(bs, 2H), 10.76(bs, 1H). LRMS:m/z(ES⁺) 217[MH⁺] 97

White foam ¹Hnmr(DMSOd₆, 400MHz) δ: 0.59(m, 1H), 1.34(m, 1H), 1.72(m,2H), 3.18(m, 2H), 3.36(m, 6H), 4.21(s, 2H), 4.34(d, 2H), 7.24(m, 2H),7.73(m, 1H), 9.58(bs, 2H), 10.95(bs, 1H). LRMS: m/z(ES⁺) 229[MH⁺] 98

White foam ¹Hnmr(DMSOd₆, 400MHz) δ: 3.01-3.40(m, 7H), 3.90(bs, 1H),4.01(bs, 1H), 4.22(m, 6H), 4.40(s, 2H), 7.28(m, 2H), 7.43(m, 1H),9.40-9.56 (m, 2H). LRMS: m/z(ES⁺) 234[MH⁺] 99

White solid ¹Hnmr(DMSOd₆, 400MHz) δ: 3.20(m, 4H), 3.37(m, 2H), 3.62(m,2H), 3.90(m, 4H), 4.22(m, 2H), 4.32(s, 2H), 7.30(m, 2H), 7.62(m, 1H),9.58(bs, 2H), 11.40(bs, 1H). LRMS: m/z(ES⁺) 233[MH⁺]

Preparation 1005-[(4-Methyl-1-piperazinyl)methyl]-1,2,3,4-tetrahydroisoquinolinetrifluoroacetate

[0631]

[0632] Trifluoroacetic acid (1 mL) was added to an ice-cooled solutionof the protected amine from preparation 44 (200 mg, 0.58 mmol) indichloromethane (3 mL), and the reaction stirred at room temperature for3 hours. The mixture was concentrated under reduced pressure and theresidue azeotroped with toluene (2×) and dichloromethane (3×) to affordthe title compound.

[0633]¹Hnmr (DMSOd₆, 400 MHz) δ: 2.79 (s, 3H), 2.81-3.04 (m, 6H), 3.38(m, 4H), 3.58 (m, 2H), 4.28 (t, 2H), 7.16 (m, 1H), 7.24 (m, 2H), 9.03(bs, 2H).

[0634] LRMS: m/z (ES⁺) 246 [MH⁺]

Preparation 1015-[(1-Methyl-4-piperidinyl)oxy]-1,2,3,4-tetrahydroisoquinoline

[0635]

[0636] Trifluoroacetic acid (5 mL) was added dropwise to a solution ofthe protected amine from preparation 47 (420 mg, 1.21 mmol) indichloromethane (5 mL), and the solution stirred at room temperature for4 hours. The solution was concentrated under reduced pressure andazeotroped twice with toluene. The residual oil was purified by columnchromatography on silica gel using an elution gradient ofdichloromethane:methanol:0.88 ammonia (97:3:0.2 to 90:10:1) to affordthe title compound as a colourless oil, 198 mg.

[0637]¹Hnmr (CDCl₃, 400 MHz) δ: 1.73 (m, 1H), 1.87 (m, 2H), 1.98 (m,2H), 2.30 (s, 3H), 2.33 (m, 2H), 2.62 (m, 2H), 2.68 (t, 2H), 3.13 (t,2H), 3.97 (s, 2H), 4.35 (m, 1H), 6.61 (d, 1H), 6.66 (d, 1H), 7.07 (dd,1H).

[0638] LRMS: m/z (ES⁺) 247 [MH⁺].

Preparation 102N,N-Dimethyl(5,6,7,8-tetrahydro[1,6]naphthyridin-2-yl)methanamine

[0639]

[0640] A solution of the protected naphthyridine from preparation 48(600 mg, 2.13 mmol) in methanol (60 mL) was purged with argon, thenheated to reflux. Immediately this was achieved, 10% palladium oncharcoal (600 mg) and ammonium formate (268 mg, 4.26 mmol) were added,and the mixture stirred under reflux for 3 minutes. The reaction vesselwas then immersed in cold water, and the cooled mixture then filteredthrough Arbocel®, washing through with ethanol. The filtrate wasevaporated under reduced pressure and the residual oil was purified bycolumn chromatography on silica gel using an elution gradient ofdichloromethane:methanol:0.88 ammonia (97:3:0.2 to 90:10:1) to affordthe title compound as a colourless oil, 259 mg.

[0641]¹H-nmr (CDCl₃, 400 MHz) δ: 2.28 (s, 6H), 2.96 (t, 2H), 3.21 (t,2H), 3.56 (s, 2H), 3.98 (s, 2H), 7.18 (d, 1H), 7.25 (d, 1H). LRMS: m/z(ES⁺) 214 [MNa⁺].

Preparations 103 to 106

[0642] The following compounds of general structure:

[0643] were prepared from the corresponding protected naphthryldines,following a similar procedure to that described in preparation 102.Prep. Yield %/ No. R Form Data 103

55 colour- less oil ¹H-nmr(CDCl₃, 400MHz) δ: 1.78(m, 4H), 2.58(m, 4H),2.94(t, 2H), 3.21(t, 2H), 3.73(s, 2H), 3.98(s, 2H), 7.17(d, 1H), 7.25(d,1H). LRMS: m/z(ES⁺) 218[MH⁺] 105

88 colour- less oil ¹H-nmr(DMSOd₆, 400MHz) δ: 1.40(m, 2H), 1.80(m, 2H),2.16(m, 2H), 2.64(m, 2H), 2.70(m, 2H), 2.98(m, 2H), 3.18(s, 3H), 3.20(m,1H), 3.44(s, 2H), 3.80(s, 2H), 7.12(d, 1H), 7.38(d, 1H). LRMS: m/z(ES⁺)262[MH⁺] 106

72 yellow oil ¹H-nmr(CDCl₃, 400MHz) δ: 2.55(m, 4H), 2.93(t, 2H), 3.21(t,2H), 3.60(s, 2H), 3.71(m, 4H), 3.98(s, 2H), 7.19(d, 1H), 7.26(d, 1H).LRMS: m/z(ES⁺) 234[MH⁺]

Preparation 107(1S,4S)-5-(5,6,7,8-Tetrahydro[1,6]naphthyridin-2-ylmethyl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0644]

[0645] 1-Chloroethyl chloroformate (79 mg, 0.55 mmol) was added to asolution of the compound from preparation 52 (168 mg, 0.5 mmol) inacetonitrile (5 mL), and the reaction warmed to 50° C., and the stirredfor 30 minutes. The cooled mixture was concentrated under reducedpressure and the residue re-dissolved in methanol (5 mL), and thesolution stirred under reflux for 45 minutes. The cooled solution waspurified directly by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (93:7:1) to afford the titlecompound as a pale orange oil, 66 mg.

[0646]¹H-nmr (CDCl₃, 400 MHz) δ: 1.80 (m, 1H), 1.99 (m, 1H), 2.71 (m,1H), 3.01 (m, 1H), 3.04 (t, 2H), 3.32 (t, 2H), 3.59 (m, 1H), 3.67 (m,1H), 3.94 (q, 2H), 4.11 (s, 2H), 4.16 (m, 1H), 4.44 (m, 1H), 7.35 (s,2H); LRMS: m/z (APCl⁺) 246 [MH⁺]

Preparation 108 N-Methyl-5,6,7.8-tetrahydro[1,6]naphthyridin-2-amine

[0647]

[0648] A mixture of the protected naphthyridine from preparation 54(1.28 g, 5.05 mmol) and 10% palladium on charcoal (130 mg) in 1Nhydrochloric acid (10.5 mL) was hydrogenated at 30° C. and 30 psi for 17hours. The reaction mixture was filtered through Arbocel®, washingthrough with water and ethanol. The combined filtrate was evaporatedunder reduced pressure and the residual solid was suspended in a warmsolution of water (20 mL) and 1N hydrochloric acid (4 mL) and themixture filtered through Arbocel®. The filtrate was concentrated underreduced pressure and azeotroped with ethanol, ethyl acetate and diethylether. The product was recrystallised from methanol and ethyl acetate toafford the title compound as a solid, 300 mg.

[0649]¹H-nmr (D₂O, 400 MHz) δ: 2.95 (s, 3H), 3.15 (m, 2H), 3.57 (m, 2H),4.20 (s, 2H), 6.84 (d, 1H), 7.59 (d, 1H).

[0650] LRMS: m/z (ES⁺) 164 [MH⁺]

Preparation 109 2-(4-Morpholinyl)-5,6,7,8-tetrahydro[1,6]naphthyridine

[0651]

[0652] Ammonium formate (1.02 g, 16 mmol), followed by 10% palladium oncharcoal (1 g) were added to a solution of the protected naphthyridinefrom preparation 55 (1 g, 3.2 mmol) in methanol (20 mL), and thereaction heated under reflux for 1.5 hours. The cooled mixture wasfiltered through Arbocel®, washing through with dichloromethane andmethanol, and the filtrate evaporated under reduced pressure. Theproduct was purified by column chromatography on silica gel using anelution gradient of dichloromethane:methanol:0.88 ammonia (98:2:0 to94:5:1) to afford the title compound, 425 mg.

[0653]¹H-nmr (CDCl₃, 400 MHz) δ: 2.79 (t, 2H), 3.17 (t, 2H), 3.44 (m,4H), 3.79 (m, 4H), 3.91 (s, 2H), 6.42 (d, 1H), 7.15 (d, 1H).

[0654] LRMS: m/z (ES⁺) 220 [MH⁺]

Preparation 1102-(4-Methyl-1-piperazinyl)-5,6,7,8-tetrahydro[1,6]naphthyridine

[0655]

[0656] The title compound was obtained in 21% yield from the protectednaphthyridine from preparation 56, following the procedure described inpreparation 109.

[0657]¹H-nmr (CDCl₃, 400 MHz) δ: 2.32 (s, 3H), 2.49 (m, 4H), 2.72 (t,2H), 3.15 (t, 2H), 3.51 (m, 4H), 3.83 (s, 2H), 6.43 (d, 1H), 7.10 (d,1H). LRMS: m/z (ES⁺) 233 [MH⁺]

Preparations 111 to 118

[0658]

[0659] Ammonium formate (5-25 eq) was added to a solution of theappropriate protected amines (1 eq) in methanol. 10% Palladium oncharcoal (1:1 w/w eq.) was added portionwise, and the mixture stirredunder reflux for 0.5 to 4 hours. The cooled mixture was filtered throughArbocel®, washing through with dichloromethane ordichloromethane:methanol (95:5) and the combined filtrates wereevaporated under reduced pressure. The crude products were purified bycolumn chromatography on silica gel using elution gradients ofdichloromethane:methanol:0.88 ammonia, to afford the title compounds.Yield %/ Prep R Form Data 111

41 clear oil ¹H-nmr(CDCl₃, 400MHz) δ: 2.22(s, 6H), 2.84(t, 2H), 3.18 (t,2H), 3.52(s, 2H), 3.98(s, 2H), 6.80(d, 1H), 8.24(d, 1H). LRMS: m/z(ES⁺)192[MH⁺] 113

69 ¹H-nmr(CDCl₃, 400MHz) δ: 1.78(m, 4H), 2.58(m, 4H), 2.86 (m, 2H),3.18(m, 2H), 3.70(s, 2H), 3.97(s, 2H), 6.81(d, 1H), 8.24 (d, 1H). LRMS:m/z (ES⁺) 218[MH^(+]) 114

65 yellow gum ¹H-nmr(CDCl₃, 400MHz) δ: 1.41(m, 2H), 1.53(m, 4H), 2.41(m, 4H), 2.90(t, 2H), 3.16(t, 2H), 3.54(s, 2H), 3.98(s, 2H), 6.81 (d,1H), 8.25(d, 1H). LRMS: m/z(ES⁺) 254]MNa⁺] 115

24 colour- less oil ¹H-nmr(CDCl₃, 400MHz) δ: 1.25(m, 4H), 1.78(m, 4H),2.92 (t, 2H), 3.16(t, 2H), 2.23(m, 2H), 3.59(s, 2H), 3.98(s, 2H), 6.80(d, 1H), 8.24(d, 1H). LRMS: m/z(ES⁺) 244[MH⁺] 116

84 orange oil ¹H-nmr(CDCl₃, 400MHz) δ: 1.58(m, 4H), 1.85(m, 2H), 2.20(m, 2H), 2.75(m, 2H), 2.90(m, 2H), 3.18(m, 4H), 3.59(s, 2H), 3.98 (s,2H), 6.80(d, 1H), 8.24(d, 1H). LRMS: m/z(ES⁺) 262[MH⁺] 117

75 colour- less oil ¹H-nmr(CDCl₃, 400MHz) δ: 2.48(m, 4H), 2.88(t, 2H),3.18 (t, 2H), 3.60(s, 2H), 3.65(m, 4H), 3.98(s, 2H), 6.81(d, 1H), 8.24(d, 1H). LRMS: m/z (ES⁺) 234[MH⁺] 118

85 oil ¹H-nmr(CDCl₃, 400MHz) δ: 1.90(d, 1H), 2.67(d, 1H), 2.88 (m, 4H),3.18(m, 2H), 3.41(s, 1H), 3.61(d, 1H), 3.82(m, 2H), 3.98(s, 2H), 4.07(d,1H), 4.37(s, 1H), 6.82 (d, 1H), 8.24(d, 1H). LRMS: m/z(ES⁺) 468[MNa⁺]

Preparation 119 5,6,7,8-Tetrahydro[2,6]naphthyridin-1-amine

[0660]

[0661] A mixture of the protected amine from preparation 68 (234 mg,0.71 mol), ammonium formate (2.34 g, 37 mmol) and 10% palladium oncharcoal (234 mg) in methanol (10 mL) was heated under reflux for 2hours. Additional ammonium formate (2.34 g, 37 mmol) and 10% palladiumon charcoal (234 mg) were added, and the mixture heated for a further 4hours. The cooled mixture was diluted with dichloromethane (50 mL),filtered through Arbocel® and the filtrate concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel using dichloromethane:methanol:0.88 ammonia (93:7:1) aseluant to afford the title compound, as a solid, 21 mg.

[0662]¹H-nmr (CDCl₃, 400 MHz) δ: 2.40 (t, 2H), 3.20 (t, 2H), 3.88 (s,2H), 4.34 (bs, 2H),6,38 (d, 1H), 7.82 (d, 1H).

[0663] LRMS: m/z (ES⁺) 150 [MH⁺]

Preparation 1205-(1-Methyl-4-piperidinyl)-1,2,3,4-tetrahydro[2,6]naphthyridinedihydrochloride

[0664]

[0665] Formic acid (150 μl, 3.92 mmol) followed by 10% palladium oncharcoal (150 mg) were added to a solution of the protectednaphthyridine from preparation 67 (630 mg, 1.96 mmol) in methanol (10mL), and the mixture heated under reflux for 4 hours. Additional 10%palladium on charcoal (350 mg) and formic acid (150 μl) were added, andthe mixture stirred under reflux for a further 18 hours. The cooledreaction mixture was filtered through Arbocel®, washing through withmethanol (300 mL), and the combined filtrates evaporated under reducedpressure. The residual oil was dissolved in 1N hydrochloric acid (6 mL),and the solution stirred under reflux for 1 hour. The cooled solutionwas concentrated under reduced pressure, azeotroped with methanol anddichloromethane to afford the title compound as a pale yellow foam, 590mg.

[0666]¹H-nmr (CD₃OD, 40 MHz) δ: 2.18 (m, 2H), 2.26 (m, 2H), 2.95 (s,3H), 3.30 (m, 4H), 3.50 (m, 1H), 3.62 (m, 4H), 4.58 (s, 2H), 7.56 (d,1H), 8.57 (d, 1H).

[0667] LRMS: m/z (ES⁺) 232 [MH⁺]

Preparation 121N,N-Dimethyl(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)methanamine

[0668]

[0669] Hydrogen chloride gas was bubbled through an ice-cooled solutionof the protected amine from preparation 71 (267 mg, 0.91 mmol) indichloromethane (15 mL), for 10 minutes, and the reaction then stirredfor a further 20 minutes at room temperature. The solution wasevaporated under reduced pressure, dissolved in methanol (5 mL), anddiluted with ethyl acetate (40 mL). The solution was evaporated underreduced pressure to afford the title compound as a buff-coloured solid.

[0670]¹H-nmr (DMSOd₆, 400 MHz) δ: 2.96 (s, 6H), 3,17 (t, 2H), 3.45 (t,2H), 4.37 (s, 2H), 4.60 (s, 2H), 8.79 (s, 1H), 10.00-10.20 (bs, 3H).LRMS: m/z (ES⁺) 193 [MH⁺]

Preparations 122 to 125

[0671] The following compounds of general structure:

[0672] were prepared from the appropriate protected amines following asimilar procedure to that described in preparation 121. Prep R Form Data122

Brown solid ¹H-nmr(DMSOd₆, 400MHz) δ: 2.90(s, 3H), 3.17(t, 2H), 3.25(s,3H), 3.37-3.60(m, 4H), 3.72 (t, 2H), 4.36(s, 2H), 4.60 (bd, 2H), 8.78(s,1H), 10.00(bs, 2H), 10.20(bs, 1H). LRMS: m/z(ES⁺) 237[MH⁺] 124

Tan solid ¹H-nmr(DMSOd₆, 400MHz) δ: 1.60-1.80 (m, 6H), 3.15(m, 2H),3.17(t, 2H), 3.45(m, 4H), 4.38(s, 2H), 4.58(s, 2H), 8.79(s, 1H),9.96-10.17 (m, 3H). LRMS: m/z(ES⁺) 233[MH⁺] 125

solid ¹H-nmr(DMSOd₆+dropTFAd, 400MHz) δ: 3.10(m, 4H), 3.36(m, 2H),3.52(m, 2H), 3.81 (m, 4H), 3.94(m, 4H), 4.30(m, 2H), 4.69(s, 2H),8.67(s, 1H), 9.85 (bs, 2H). LRMS: m/z (ES⁺) 279[MH⁺]

Preparation 1264-(1-Pyrrolidinylmethyl)-5.6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0673]

[0674] A solution of the protected amine from preparation 69 (395 mg,1.28 mmol) in methanol (25 mL), was allowed to stand under a nitrogenatmosphere. 10% Palladium on charcoal (395 mg), followed by ammoniumformate (1.0 g, 15.9 mmol) was added, and the mixture stirred vigorouslyunder reflux for 30 minutes. The cooled mixture was diluted withdichloromethane (100 mL), filtered through Arbocel® and the filtrateconcentrated under reduced pressure. The crude product was purified bycolumn chromatography using dichloromethane:methanol:0.88 ammonia(97:3:1) as eluant to afford the title compound as a colourless oil,that crystallised on standing, 174 mg.

[0675]¹H-nmr (CDCl₃, 400 MHz) δ: 1.78 (m, 4H), 2.57 (m, 4H), 2,85 (t,2H), 3,15 (t, 2H), 3.68 (s, 2H), 4.04 (s, 2H), 8.89 (s, 1H).

[0676] LRMS: m/z (ES⁺) 219 [MH⁺]

Preparation 1274-(1-Piperidinylmethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0677]

[0678] The title compound was obtained as an orange oil in 43% yieldfrom the protected amine from preparation 72, following the proceduredescribed in preparation 126.

[0679]¹H-nmr (CDCl₃, 400 MHz) δ: 1.42 (m, 2H), 1.55 (m, 4H), 2.41 (m,4H), 2.89 (t, 2H), 3.14 (t, 2H), 3.50 (s, 2H), 4.05 (s, 2H), 8.87 (s,1H).

[0680] LRMS: m/z (ES⁺) 233 [MH⁺]

Preparation 1284-[(4-Methoxy-1-piperidinyl)methyl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0681]

[0682] The title compound was obtained in 42% yield as a yellow oil,from the protected amine from preparation 76, following a similarprocedure to that described in preparation 126.

[0683]¹H-nmr (CDCl₃, 400 MHz) δ: 1.56 (m, 2H), 1.84 (m, 2H), 2.24 (m,2H), 2.73 (m, 2H), 2.88 (t, 2H), 3.15 (t, 2H), 3.20 (m, 1H), 3.32 (s,3H), 3.53 (s, 2H), 4.05 (s, 2H), 8.87 (s, 1H).

[0684] LRMS: m/z (ES⁺) 263 [MH⁺]

Preparation 129 5,6,7,8-Tetrahydroimidazo[1,5-a]pyrazine hydrochloride

[0685]

[0686] 10% Palladium on charcoal (100 mg) was added portionwise to asolution of the protected amine from preparation 79 (900 mg, 4.22 mmol)in methanol (10 mL), followed by formic acid (0.25 mL), and the reactionstirred under reflux for 5 hours. The cooled mixture was diluted withwater (5 mL), filtered through Arbocel®, and washed through withmethanol (200 mL). The filtrate was concentrated under reduced pressureand azeotroped with dichloromethane. The residual oil was dissolved in1N hydrochloric acid (10 mL), and the solution stirred under reflux for2 hours. The cooled solution was evaporated under reduced pressure andthe resulting solid recrystallised from methanol to afford the titlecompound as a white solid, 500 mg.

[0687]¹H-nmr (DMSOd₆, 400 MHz) δ: 3.58 (t, 2H), 4.40 (s, 2H), 4.50 (t,2H), 7.56 (s, 1H), 9.10 (s, 1H).

[0688] LRMS: m/z (ES⁺) 125 [MH⁺]

Preparation 130 3-Methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinehydrochloride

[0689]

[0690] Ammonium formate (3.33 g, 52.8 mmol) and 10% palladium oncharcoal (800 mg) were added to a solution of the protected amine frompreparation 81 (800 mg, 3.52 mmol) in methanol (10 mL) and 2Nhydrochloric acid (0.5 mL), and the reaction heated under reflux for 25hours. The cooled mixture was diluted with water (5 mL), then filteredthrough Arbocel®. The filtrate was evaporated under reduced pressure,and the residual solid purified by column chromatography on silica gelusing an elution gradient of dichloromethane:methanol:0.88 ammonia(100:0:0 to 90:10:1) to give a solid. This was dissolved in 2Nhydrochloric acid (10 mL), the solution heated under reflux for 2 hours,then cooled and evaporated under reduced pressure, azeotroping withdichloromethane, to afford the title compound as a white solid, 536 mg.

[0691]¹H-nmr (CD₃OD, 400 MHz) δ: 2.66 (s, 3H), 3.81 (t, 2H), 4.44 (t,2H), 4.57 (s, 2H), 7.46 (s, 1H).

[0692] LRMS: m/z (ES⁺) 138 [MH⁺]

Preparation 131 3-Ethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

[0693]

[0694] Ammonium formate (2.12 g, 33.6 mmol) and 10% palladium oncharcoal (550 mg) were added to a solution of the protected amine frompreparation 80 (541 mg, 2.24 mmol) in methanol (15 mL) and 2Nhydrochloric acid (0.5 mL), and the reaction heated under reflux for 26hours. The cooled mixture was diluted with water (5 mL), then filteredthrough Arbocel®, washing through with dichloromethane:methanol solution(1:1, 300 mL). The filtrate was evaporated under reduced pressure, andthe residual solid was dissolved in 2N hydrochloric acid (10 mL), thesolution heated under reflux for 2 hours, then cooled and evaporatedunder reduced pressure. The residual orange gum was purified by columnchromatography on silica gel using an elution gradient ofdichloromethane:methanol:0.88 ammonia (97:3:0 to 90:10:1) to give thetitle compound as an orange solid, 68 mg.

[0695]¹H-nmr (CD₃OD, 400 MHz) δ: 1.24 (t, 3H), 2.67 (q, 2H), 3.15 (t,2H), 3.88 (t, 2H), 3.95 (s, 2H), 6.59 (s, 1H).

[0696] LRMS: m/z (ES⁺) 138 [MH⁺]

Preparation 132N,N-Dimethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine

[0697]

[0698] Ammonium formate (2.0 g, 31.7 mmol) and 10% palladium on charcoal(200 mg) were added to a solution of the protected amine frompreparation 85 (170 mg, 0.66 mmol) in ethereal hydrochloric acid (2 mL,1M) and methanol (20 mL), and the mixture heated under reflux for 20minutes. The cooled mixture was diluted with dichloromethane (50 mL),filtered through Arbocel®, and, the filtrate concentrated under reducedpressure. The residue was purified by column chromatography on silicagel using dichloromethane:methanol:0.88 ammonia (93:7:1) as eluant toafford the title compound as a colourless gum, 72 mg.

[0699]¹H-nmr (CDCl₃, 400 MHz) δ: 1.70 (bs, 1H), 2.74 (s, 6H), 3.13 (t,2H), 3.73 (t, 2H), 3.98 (s, 2H), 6.46 (s, 1H).

[0700] LRMS: m/z (ES⁺) 167 [MH⁺]

Preparation 133N-(2-Methoxyethyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine

[0701]

[0702] The title compound was obtained as a yellow oil, from theprotected amine from preparation 86, following the procedure describedin preparation 132.

[0703]¹H-nmr (CDCl₃, 400 MHz) δ: 2.78 (s, 3H), 3.13 (t, 2H), 3.18 (t,2H), 3.32 (s, 3H), 3.48 (t, 2H), 3.76 (t, 2H), 3.97 (t, 2H), 6.48 (s,1H). LRMS: m/z (ES⁺) 211 [MH⁺]

Preparation 134 3-Isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinedihydrochloride and Preparation 1352-(5,6,7,8-Tetrahydroimidazo[1,5-a]pyrazin-3-yl)-2-propanoldihydrochloride

[0704]

[0705] A mixture of the compounds from preparations 87 and 88 (460 mg,1.47 mmol), glacial acetic acid (0.5 mL) and 10% palladium on charcoal(300 mg) was hydrogenated at 50 psi and 70° C. for 36 hours. The cooledmixture was diluted with water (10 mL), filtered through Arbocel®,washing through with methanol (500 mL). The filtrate was evaporatedunder reduced pressure, and the residual oil was purified by columnchromatography on silica gel using an elution gradient ofdichloromethane:methanol:0.88 ammonia (97:3:0 to 92:8:1) to give anorange oil. This was dissolved in methanol, 1N ethereal hydrochloricacid added, and the mixture evaporated under reduced pressure to give amixture of the title compounds as a light brown foam, 165 mg.

[0706]¹H-nmr (CD₃OD, 400 MHz) δ: 1.42 (d, 6H), 1.71 (s, 6H), 3.45 (m,1H), 3.78 (m, 2H), 3.78 (m, 2H), 4.50 (m, 2H), 4.58 (m, 2H), 4.58 (m,2H), 4.80 (m, 2H), 7.46 (s, 1H).

Preparation 136 5,6,7,8-Tetrahydroimidazo[1,5-a]pyrazin-3-amine

[0707]

[0708] 10% Palladium on charcoal (200 mg) and ammonium formate (2 g)were added carefully to a solution of the compound from preparation 84(152 mg, 0.6 mmol) in 1N ethereal hydrochloric acid (2 mL) and methanol(20 mL). The mixture was heated under reflux for 1.5 hours, then cooled.Additional 1N ethereal hydrochloric acid (1 mL), 10% palladium oncharcoal (200 mg) and ammonium formate (2 g) were added, and the mixtureheated under reflux for a further 20 minutes. The cooled mixture wasdiluted with dichloromethane (50 mL), filtered through Arbocel®, and thefiltrate concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (93:7:1 to 80:20:2) to afford thetitle compound as an oil, 35 mg.

[0709]¹H-nmr (DMSOd₆, 400 MHz) δ: 3.12 (t, 2H), 3.57 (t, 2H), 3.87 (s,2H), 6.27 (s, 1H).

[0710] LRMS: m/z (ES⁺) 139 [MH⁺]

Preparation 137 3-Ethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinedihydrochloride

[0711]

[0712] A mixture of the protected amine from preparation 92 (605 mg,2.12 mmol), acetic acid (8 mL), and 1N ethereal hydrobromic acid (30 mL)in toluene (25 mL) was stirred at 100° C. for 4 hours. The mixture wascooled, concentrated under reduced pressure, and azeotroped with toluene(2×25 mL). The residue was dissolved in 1 N ethereal hydrochloric acid,then evaporated under reduced pressure to afford the title compound as atan coloured solid, 405 mg.

[0713]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.10 (t, 3H), 2.60 (m, 2H), 3.60 (m,2H), 4.32 (m, 2H) 4.62 (s, 2H), 7.50 (s, 1H).

[0714] LRMS: m/z (ES⁺) 152 [MH⁺]

Preparation 1387-Benzyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-3-carbaldehyde

[0715]

[0716] n-Butyllithium (1.6M in hexane, 9 ml, 14.4 mmol) was added to theimidazopyrazine from preparation 79 (2.8 g, 13.13 mmol) intetrahydrofuran (20 ml) under a nitrogen atmosphere at −78° C. at a ratethat maintained the reaction temperature below −70° C. The mixture waswarmed to 0° C. and was stirred for 10 minutes and then cooled to −78°C. N,N-Dimethylformamide (1.5 ml, 19.4 mmol) was added dropwise and themixture was warmed to 0° C. and was stirred for 10 minutes. Saturatedsodium hydrogen carbonate solution (40 ml), then water (100 ml) wereadded and the aqueous solution was extracted with ethyl acetate (100ml). The organic solution was washed with water (50 ml), then brine (50ml), dried over magnesium sulphate and evaporated under reducedpressure. The residue was purified by chromatography on silica gel usingethyl acetate in pentane as eluant (gradient from 70:30 to 90:10) togive the title compound as a yellow solid (2.67 g).

[0717]¹H-nmr (CDCl₃, 400 MHz) δ: 2.89 (t, 2H), 3.72 (m, 4H), 4.44 (t,2H), 7.02 (s, 1H), 7.35 (m, 5H), 9.72 (s, 1H)

[0718] LRMS: m/z (ES⁺) 264 [MNa⁺]

Preparation 1397-Benzyl-3-morpholin-4-ylmethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine

[0719]

[0720] Morpholine (260 μl, 3.0 mmol) was added to the aldehyde frompreparation 138 in tetrahydrofuran (10 ml) under a nitrogen atmosphereand the mixture was stirred for 1 hour. Sodium triacetoxyborohydride(790 mg, 3.73 mmol) was added portionwise and the reaction mixture wasstirred at room temperature for 16 hours. Water (20 ml) was added andthe solution was extracted with ethyl acetate (2×100 ml). The combinedorganic solutions were dried over magnesium sulphate and evaporatedunder reduced pressure. The residue was purified by chromatography onsilica gel using methanol in dichloromethane as eluant (gradient from1:99 to 5:95) to give the title compound as a golden oil (680 mg).

[0721]¹H-nmr (CDCl₃, 400 MHz) δ: 2.46 (m, 4H), 2.84 (t, 2H), 3.55 (s,2H), 3.66 (m, 4H), 4.06 (t, 2H), 6.65 (s, 1H), 7.31 (m, 5H)

[0722] LRMS: m/z (ES⁺) 335 [MNa⁺]

Preparation 140(7-Benzyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-3-yl)-methanol

[0723]

[0724] Sodium borohydride (250 mg, 6.6 mmol) was added portionwise tothe aldehyde from preparation 138 (1.45 g, 6 mmol) in methanol (25 ml)under a nitrogen atmosphere. The mixture was stirred at room temperaturefor 1 hour and further sodium borohydride (45 mg, 2 mmol) was added. Themixture was stirred at room temperature for 30 minutes and saturatedsodium hydrogen carbonate solution (40 ml) and water (40 ml) were added.The aqueous mixture was extracted with ethyl acetate (3×100 ml) and thecombined organic solutions were dried over magnesium sulphate andevaporated under reduced pressure. The residue was co-evaporated withdichloromethane (×2) and the residue was dried under vacuum to give thetitle compound as a gum (1.45 g)

[0725]¹H-nmr (CDCl₃, 400 MHz) δ: 2.86 (t, 2H), 3.62 (s, 2H), 3.70 (s,2H), 4.07 (t, 2H), 4.61 (s, 2H), 6.62 (s, 1H), 7.32 (m, 5H)

[0726] LRMS: m/z (ES⁺) 266 [MNa⁺]

Preparation 1417-Benzyl-3-(4-methoxy-piperidin-1-yl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine

[0727]

[0728] A stirred mixture of the bromo compound from preparation 83 (584mg, 2 mmol) 4-methoxypiperidine (3 g, 26 mmol) andtetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol) was purgedwith argon and then heated to 150° C. for 17 hours. The reaction mixturewas cooled to room temperature and partitioned between dichloromethane(100 ml) and water (100 ml). The organic phase was separated, dried overmagnesium sulphate and evaporated under reduced pressure. The residuewas purified by chromatography on silica gel using methanol in ethylacetate as eluant (gradient from 2:98 to 6:94). The material obtainedwas dissolved in dichloromethane (50 ml), washed with 5% sodiumcarbonate solution (50 ml), water (50 ml) dried over magnesium sulphateand evaporated under reduced pressure. The residue was purified bychromatography on silica gel using methanol in ethyl acetate as eluant(gradient from 2:98 to 6:94) to give the title compound as a yellow oil(202 mg).

[0729]¹H-nmr (CDCl₃, 400 MHz) δ: 1.65 (m, 2H), 2.02 (m, 2H), 2.78 (t,2H), 2.88 (m, 2H), 3.25 (m, 3H), 3.37 (s, 3H), 3.62 (s, 2H), 3.67 (s,2H), 3.79 (t, 2H), 6.45 (s, 1H), 7.30 (m, 5H)

[0730] LRMS: m/z (ES⁺) 327 [MH⁺]

Preparation 142N′-(6-Benzyl-5,6,7,8-tetrahydro-[2,6]naphthyridin-1-yl)-N,N-dimethyl-ethane-1,2-diamine

[0731]

[0732] A mixture of the bromo compound from preparation 34 (1 g, 3.3mmol) and N,N-dimethylethylenediamine (5 ml) were heated at 140° C. inan autoclave for 20 hours. The mixture was cooled to room temperatureand was added to 0.05M sodium hydroxide solution. The solution wasextracted with dichloromethane (3×60 ml) The combined organic solutionswere dried over magnesium sulphate and evaporated under reducedpressure. The residue was purified by chromatography on silica gel usingmethanol and ammonium hydroxide in dichloromethane as eluant (gradientfrom 0:1:99 to 20:1:79) to give the title compound as a yellow oil (971mg).

[0733]¹H-nmr (CDCl₃, 400 MHz) δ: 2.26 (s, 6H), 2.47 (t, 2H), 2.55 (t,2H), 2.80 (t, 2H), 3.50 (m, 4H), 3.68 (s, 2H), 4.80 (s, 1H), 6.23 (d,1H), 7.33 (m, 5H), 7.88 (d, 1H)

[0734] LRMS: m/z (ES⁺) 311 [MH⁺]

Preparation 143(6-Benzyl-5,6,7,8-tetrahydro-[2,6]naphthyridin-1-yl)-pyridin-2-ylmethyl-amine

[0735]

[0736] The bromo compound from preparation 34 (303 mg, 1 mmol) was mixedwith 2-aminomethylpyrimidine (2 ml) and the mixture was heated at 170°C. under a nitrogen atmosphere for 5 hours. The reaction mixture wascooled and partitioned between ethyl acetate and 0.02 M sodium hydroxidesolution. The organic solution was dried over magnesium sulphate andevaporated under reduced pressure. The residue was purified bychromatography on silica gel using dichloromethane and ethyl acetate andthen methanol in ethyl acetate as eluant (gradient from 100:0 to 0:100dichloromethane and ethyl acetate followed by methanol in ethyl acetate0:100 to 5:95) to give the title compound as a pale yellow oil thatcrystallised on standing (216 mg).

[0737] LRMS: m/z (ES⁺) 331 [MH⁺]

Preparation 144(6-Benzyl-5,6,7,8-tetrahydro-[2,6]naphthyridin-1-ylmethyl)-(2-methoxy-ethyl)-methyl-amine

[0738]

[0739] Acetic acid (480 mg, 8 mmol) was added to a solution of thealdehyde from preparation 35 and N-(2-methoxyethyl)methylamine (356 mg,4 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred for 10minutes. Sodium triacetoxyborohydride (2.12 g, 10 mmol) was added andthe mixture was stirred at room temperature for 2.5 hours. 2MHydrochloric acid was added and the mixture was basified with 1M sodiumhydroxide and extracted with ethyl acetate. The combined organicsolutions were dried over magnesium sulphate and evaporated underreduced pressure. The residue was purified by chromatography on silicagel using methanol in dichloromethane as eluant (gradient from 0:100 to10:90) to give the title compound as a yellow oil (544 mg).

[0740]¹H-nmr (CDCl₃, 400 MHz) δ: 2.27 (s, 3H), 2.66 (t, 2H), 2.79 (t,2H), 3.00 (t, 2H), 3.28 (s, 3H), 3.48 (t, 2H), 3.60 (s, 2H), 3.66 (s,2H), 3.68 (s, 2H), 6.80 (d, 1H), 7.34 (m, 5H), 8.25 (d, 1H)

[0741] LRMS: m/z (ES⁺) 326 [MH⁺]

Preparation 145(7-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-2-yl)-dimethyl-amine

[0742]

[0743] 1-Benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester (10 g,38.3 mmol) was added to a mixture of dimethyl guanidinium sulphate (4.6g, 25 mmol) and potassium carbonate (9.28 g, 67 mmol) in methanol andthe reaction mixture was stirred at room temperature for 48 hours. Themixture was filtered and the solid obtained was recrystallised fromethanol.

[0744] The material isolated was dissolved in phosphorous oxychloride(20 ml) and heated at 90° C. for 1 hour. The mixture was concentratedunder reduced pressure and the residue was dissolved in dichloromethane(50 ml) and was added to sodium hydrogen carbonate solution. The aqueouslayer was extracted with dichloromethane (2×50 ml) and the combinedorganic solutions were dried over magnesium sulphate and evaporatedunder reduced pressure to give the title compound as a brown oil (3.03g).

[0745]¹H-nmr (CDCl₃, 400 MHz) δ: 2.70 (m, 4H), 3.12 (s, 6H), 3.48 (s,2H), 3.68 (s, 2H), 7.33 (m, 5H)

[0746] LRMS: m/z ES⁺ 303, 305 [MH⁺]

Preparation 146 7-Benzyl-N*2*,N*2*-dimethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine-2,4-diamine

[0747]

[0748] Ammonia was bubbled through a solution of the chloro compoundfrom preparation 145 (1.51 g, 5 mmol) in dimethylsulphoxide (20 ml) togive a saturated solution and the mixture was heated at 140° C. in anautoclave for 18 hours. The reaction mixture was cooled to roomtemperature and was dissolved in ethyl acetate. The organic solution waswashed with water and brine (×2) and then was dried over magnesiumsulphate and evaporated under reduced pressure. The residue was purifiedby chromatography on silica gel using methanol in dichloromethane aseluant (gradient from 0:100 to 6:94) to give the title compound as abrown solid (0.54 g).

[0749]¹H-nmr (DMSOd₆, 400 MHz) δ: 2.40 (t, 2H), 2.73 (t, 2H), 3.05 (s,6H), 3.41 (s, 2H), 3.67 (s, 2H), 4.45 (s, 2H), 7.33 (m, 5H)

[0750] LRMS: m/z ES⁺ 284 [MH⁺]

Preparation 1477-Benzyl-N*4*-(2-methoxy-ethyl)-N*2*,N*2*-dimethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine-2,4-diamine

[0751]

[0752] The chloro compound from preparation 145 (1.51 g, 5 mmol) and2-methoxyethylamine (2 ml, 23 mmol) were dissolved in ethanol (20 ml)and the solution was heated under reflux for 48 hours. The solvent wasevaporated under reduced pressure and the residue was diluted with2-methoxyethylamine (6 ml, 69 mmol) and was heated under reflux for 8hours. The reaction mixture was cooled to room temperature and was addedto ethyl acetate. The solution was washed with 0.1M sodium hydroxidesolution and brine, dried over magnesium sulphate and evaporated underreduced pressure to give the title compound (1.57 g).

[0753]¹H-nmr (CDCl₃, 400 MHz) δ: 2.35 (t, 2H), 2.73 (t, 2H), 3.07 (s,6H), 3.35 (s, 3H), 3.40 (s, 2H), 3.53 (t, 2H), 3.66 (m, 4H), 4.62 (t,1H), 7.23 (m, 1H), 7.31 (m, 2H), 7.35 (d, 2H)

[0754] LRMS: m/z ES⁺ 342 [MH⁺]

Preparation 148(6-Benzyl-5,6,7,8-tetrahydro-[1,6]naphthyridin-2-yl)-(2-methoxy-ethyl)-amine

[0755]

[0756] Copper (II) sulphate (200 mg) was added to a solution of6-benzyl-2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine (4.5 g, 17.4mmol)(see reference WO9830560 Example 33 b) in 2-methoxyethylamine andthe mixture was heated under reflux for 20 hours. The mixture wasevaporated under reduced pressure and the residue was partitionedbetween dichloromethane (100 ml) and water (50 ml). The aqueous phasewas extracted with dichloromethane (2×50 ml) and the combined organicphases were dried over magnesium sulphate and evaporated under reducedpressure. The residue was purified by chromatography on silica gel usingmethanol in dichloromethane as eluant (gradient from 1:99 to 3:97) togive the title compound as an orange oil (1.32 g).

[0757] LRMS: m/z ES⁺ 298.2 [MH⁺]

Preparation 149(6-Benzyl-5,6,7,8-tetrahydro-[1,6]naphthyridin-2-yl)-pyridin-2-ylmethyl-amine

[0758]

[0759] The title compound was obtained from6-benzyl-2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine(see referenceWO9830560 Example 33b) and 2-aminomethylpyridine in 50% yield followingthe procedure described in preparation 148.

[0760] LRMS: m/z ES⁺331.2 [MH⁺]

Preparation 1506-Benzyl-5,6,7,8-tetrahydro-[1,6]naphthyridine-2-carbonitrile

[0761]

[0762] 6-Benzyl-2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine (129 mg,0.5 mmol) (See Reference WO9830560 Example 33b) was added to zinccyanide (58.7 mg, 0.5 mmol), lithium chloride (27 mg, 0.65 mmol) andtetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) inN,N-dimethylformamide (3 ml). The mixture was purged with argon and washeated at 100° C. for 17 hours. The reaction mixture was cooled to roomtemperature and a further quantity oftetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) was addedand the mixture was heated at 125° C. for 3 hours. The reaction mixturewas cooled to room temperature and a further quantity oftetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) was addedand the mixture was heated at 125° C. for 3 hours. The reaction mixturewas cooled to room temperature and was partitioned between ethyl acetate(40 ml) and water (40 ml). The phases were separated and the organicphase was washed with water (3×30 ml) dried over magnesium sulphate andevaporated under reduced pressure. The residue was purified bychromatography on silica gel using ethyl acetate in pentane as eluant(33:67) to give the title compound as a brown gum (97 mg).

[0763]¹H-nmr (CDCl₃, 400 MHz) δ: 2.88 (t, 2H), 3.09 (t, 2H), 3.68 (s,2H), 3.73 (s, 2H), 7.23 (m, 7H)

[0764] LRMS: m/z ES⁺ 250 [MH⁺].

Preparation 151(6-Benzyl-5,6,7,8-tetrahydro-[1,6]naphthyridin-2-yl)-methylamine

[0765]

[0766] Anhydrous cobalt chloride (389 mg, 3 mmol) was added to thenitrile from preparation 150 (373 mg, 1.5 mmol) in methanol (10 ml) andthe mixture was stirred at room temperature for 10 minutes. Sodiumborohydride (567 mg, 15 mmol) was added portionwise over 15 minutes andthe reaction mixture was stirred at room temperature for 1.5 hours. 3NHydrochloric acid (7 ml) was added dropwise over 10 minutes and themixture was stirred at room temperature for 20 minutes. The solution wasneutralised by addition of concentrated aqueous ammonia and the mixturewas stirred at room temperature for 72 hours. Silica gel (10 g) wasadded and the mixture was evaporated under reduced pressure. The residuewas purified by chromatography on silica gel using ammonium hydroxideand methanol in dichloromethane as eluant (2:15:85). The materialobtained was co evaporated with methanol and then with dichloromethaneto give the title compound as a pale brown gum (135 mg).

[0767]¹H-nmr (CDCl₃, 400 MHz) δ: 2.86 (t, 2H), 3.00 (t, 2H), 3.60 (s,2H), 3.70 (s, 2H), 3.90 (s, 2H), 7.30 (m, 7H)

[0768] LRMS: m/z (ES⁺) 254 [MH⁺]

Preparation 152(6-Benzyl-5,6,7,8-tetrahdro-[1,6]naphthyridin-2-ylmethyl)-carbamic acidtert-butyl ester

[0769]

[0770] Di-tert-butyl dicarbonate (300 mg, 1.37 mmol) in dichloromethane(2 ml) was added to the amine from preparation 151 (288 mg, 1.14 mmol)in dichloromethane (10 ml) and the mixture was stirred at roomtemperature for 72 hours. The solvent was evaporated under reducedpressure and the residue was purified by chromatography on silica gelusing ammonium hydroxide and methanol in dichloromethane as eluant(0.5:5:95). The material obtained was further purified by chromatographyon silica gel using ammonium hydroxide and propan-2-ol in pentane aseluant (gradient from 0.5:10:90 to 0.7:15:85). The material isolated wasco-evaporated with methanol to give the title compound as a colourlessgum (251 mg).

[0771]¹H-nmr (CDCl₃, 400 MHz) δ: 1.46 (s, 9H), 2.95 (t, 2H), 3.00 (t,2H), 3.60 (d, 2H), 3.71 (s, 2H), 4.35 (d, 2H), 5.41 (s, 1H), 7.00 (d,1H), 7.30 (m, 6H)

[0772] LRMS: m/z (ES⁺) 354 [MH⁺]

Preparation 153 tert-Butyl(2E)-3-(6-benzyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2-yl)-2-propenoate

[0773]

[0774] Tri-tert-butylphosphine (3.0 g, 15.28 mmol) was added to asolution of tris(dibenzylideneacetone)dipalladium (4.2 g, 4.63 mmol) in1,4-dioxane (45 ml), under argon, and the solution stirred for 30minutes at room temperature. This solution was then added to a mixtureof 6-benzyl-2-chloro-5,6,7,8-tetrahydro[1,6]naphthyridine (WO 9830560Example 33b) (12 g, 46.3 mmol) and tert-butylacrylate (20.3 ml, 139mmol) in triethylamine (45 ml), and the reaction was stirred underreflux for 17 hours. The cooled mixture was concentrated under reducedpressure and the residue partitioned between ethyl acetate (300 ml) andwater (300 ml) and this mixture filtered through Arbocel®. The pH of themixture was adjusted to 8 using sodium bicarbonate, the phasesseparated, and the aqueous layer re-extracted with ethyl acetate (2×100ml). The combined organic solutions were dried over magnesium sulphateand evaporated under reduced pressure. The crude product waspre-adsorbed onto silica gel, and purified by column chromatographyusing an elution gradient of cyclohexane: ethyl acetate (84:16 to 66:34)to afford the title compound as an orange-red oil, (15.8 g).

[0775]¹H-nmr (CDCl₃, 400 MHz) δ: 1.50 (s, 9H), 2.82 (t, 2H), 3.02 (t,2H), 3.61 (s, 2H), 3.70 (s, 2H), 6.75 (d, 1H), 7.18 (d, 1H), 7.26 (m,2H), 7.35 (m, 4H), 7.55 (d, 1H).

[0776] LRMS: m/z (ES⁺) 373 [MNa⁺]

Preparation 154 tert-Butyl(2R,3R)-3-(6-benzyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2-yl)-2,3-dihydroxypropanoate

[0777]

[0778] Osmium tetroxide (8.3 ml, 2.5% wt.in tert-butanol) was addeddropwise to a mixture of the compound from preparation 153 (11.3 g, 32.2mmol), N-methylmorpholine N-oxide (4.15 g, 35.4 mmol) in water (80 ml)and acetone (160 ml), and the reaction was stirred at room temperaturefor 72 hours. The mixture was concentrated under reduced pressure, andthe residue azeotroped with acetone. The crude product was purified bycolumn chromatography on silica gel using an elution gradient ofcyclohexane: ethyl acetate (80:25 to 25:75), to afford the titlecompound as a gum (7.2 g).

[0779]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.38 (s, 9H), 2.77 (m, 2H), 2.81 (m,2H), 3.52 (s, 2H), 3.62 (s, 2H), 4.20 (d, 1H), 4.78 (d, 1H), 4.82 (d,1H), 5.40 (d, 1H), 7.22 (m, 2H), 7.30 (m, 4H), 7.38 (d, 1H).

[0780] LRMS: m/z (ES⁺) 407 [MNa⁺]

Preparation 1552-{[(6-Benzyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2-yl)methyl]amino}ethanol

[0781]

[0782] Acetic acid (368.7 mg, 6.14 mmol) and ethanolamine (187.5 mg,3.07 mmol) were added dropwise to a solution of the aldehyde frompreparation 29b (595 mg, 2.36 mmol), and the mixture purged with argon,then heated under reflux for 2 hours. Sodium triacetoxyborohydride (1 g,4.72 mmol) was added to the cooled solution, and the reaction stirred atroom temperature for 17 hours. 2M Hydrochloric acid (12 ml) was added,the solution stirred for 15 minutes, then partitioned betweendichloromethane (150 ml) and water (150 ml), and the layers separated.The pH of the aqueous layer was adjusted to 12 using 5% aqueous sodiumcarbonate solution, re-partitioned with the separated organic phase, andfurther extracted with dichloromethane (3×60 ml). These combined organicsolutions were dried over magnesium sulphate and evaporated underreduced pressure. The residual oil was purified by column chromatographyon silica gel using an elution gradient of dichloromethane: methanol:0.88 ammonia (97:3:0.2 to 90:10:10) to afford the title compound as acolourless oil (450 mg).

[0783]¹H-nmr (CDCl₃, 400 MHz) δ: 2.76 (m, 4H), 3.04 (t, 2H), 3.60 (s,2H), 3.62 (t, 2H), 3.72 (s, 2H), 3.90 (s, 2H), 7.02 (d, 1H), 7.25 (m,6H).

[0784] LRMS: m/z (ES⁺) 320 [MNa⁺]

Preparation 156N-[(6-Benzyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2-yl)methyl]-2-methoxy-N-methylethanamine

[0785]

[0786] The title compound was obtained as a yellow oil in 89% yield fromthe aldehyde from preparation 29b and N-(2-methoxyethyl)methylamine,following a similar procedure to that described in preparation 155.

[0787]¹H-nmr (CDCl₃, 400 MHz) δ: 2.30 (s, 3H), 2.64 (t, 2H), 2.83 (t,2H), 3.01 (t, 2H), 3.21 (s, 3H), 3.51 (t, 2H), 3.59 (s, 2H), 3.66 (s,2H), 3.69 (s, 2H), 7.20-7.38 (m, 7H).

[0788] LRMS: m/z (ES⁺) 348 [MNa⁺]

Preparation 157 6-Benzyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2-yltrifluoromethanesulfonate

[0789]

[0790] Trifluoromethanesulphonic anhydride (770 μl, 4.58 mmol) was addeddropwise to a cooled (−30° C.) solution of the compound from preparation27 (1 g, 4.16 mmol) and triethylamine (640 μl, 4.58 mmol) indichloromethane (20 ml), so as to maintain the temperature below −20° C.The solution was then allowed to warm slowly to room temperature andstirred for a further 2 hours. The solution was diluted withdichloromethane (30 ml), washed with water (10 ml), dried over magnesiumsulphate and evaporated under reduced pressure. The residual brown oilwas purified by column chromatography on silica gel using an elutiongradient of pentane: dichloromethane: methanol (5:95:0 to 0:100:0 to0:97:3) to afford the title compound as an orange oil (980 mg).

[0791]¹H-nmr (CDCl₃, 400 MHz) δ: 2.84 (t, 2H), 3.00 (t, 2H), 3.62 (s,2H), 3.71 (s, 2H), 6.91 (d, 1H), 7.25-7.40 (m, 5H), 7.43 (d, 1H). LRMS:m/z (ES⁺) 373 [MH⁺]

Preparation 158 tert-Butyl4-(6-benzyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2-yl)-1-piperidinecarboxylate

[0792]

[0793] A mixture of 1,2-dibromoethane (22 μl, 0.26 mmol) and activatedzinc (640 mg, 9.80 mmol) in N,N-dimethylformamide (1.5 ml) was heated to50° C. for 5 minutes, then allowed to cool to room temperature.Trimethylsilylchloride (32.7 μl, 0.26 mmol) was added, the mixtureheated again to 50° C., re-cooled to room temperature and tert-butyl4-iodo-1-piperidinecarboxylate (EP 1078928 preparation 15-2) (2.0 g,6.45 mmol) added. This mixture was re-heated to 50° C. for 5 minutes,cooled again, and a solution of the compound from preparation 157 (960mg, 2.58 mmol) in N,N-dimethylformamide (1 ml), followed bytris(dibenzylideneacetone)dipalladium (0) (29.6 mg, 0.05 mmol) andtri(2-furyl)phosphine (24 mg, 0.10 mmol) added and the reaction mixturestirred at 60° C. for 2 hours. The cooled mixture was partitionedbetween water (15 ml) and dichloromethane (50 ml), filtered throughArbocel® and the filtrate separated. The aqueous phase was extractedwith dichloromethane (30 ml), and the combined organic solutions driedover magnesium sulphate and evaporated under reduced pressure. Theresidual orange oil was purified by column chromatography on silica gelusing an elution gradient of dichloromethane: methanol (100:0 to96.5:3.5) to afford the title compound as an orange oil (717 mg).

[0794]¹H-nmr (CDCl₃, 400 MHz) δ: 1.45 (s, 9H), 1.63 (m, 2H), 1.87 (m,2H), 2.84 (m, 4H), 3.00 (m, 2H), 3.58 (s, 2H), 3.69 (s, 2H), 3.83 (m,1H), 4.22 (bs, 2H), 6.88 (d, 1H), 7.20 (d, 1H), 7.32 (m, 5H).

[0795] LRMS: m/z (ES⁺) 430 [MNa⁺]

Preparation 1596-Benzyl-2-(4-piperidinyl)-5,6,7,8-tetrahydro[1,6]naphthyridinedihydrochloride

[0796]

[0797] An ice-cooled solution of the protected amine from preparation158 (700 mg, 1.72 mmol) in dichloromethane (20 ml) was saturated withhydrogen chloride, and the solution then stirred for 2 hours at 0° C.The reaction mixture was then degassed under nitrogen and evaporatedunder reduced pressure to afford the title compound as an orange foam(654 mg).

[0798]¹H-nmr (CD₃OD, 400 MHz) δ: 2.10 (m, 2H), 2.22 (m, 2H), 3.18 (m,2H), 3.33 (s, 2H), 3.53 (m, 4H), 3.80 (m, 1H), 4.58 (m, 4H), 7.53 (m,4H), 7.63 (m, 3H).

[0799] LRMS: m/z (ES⁺) 308 [MH⁺]

Preparation 1606-Benzyl-2-(1-methyl-4-piperidinyl)-5,6,7,8-tetrahydro[1,6]naphthyridine

[0800]

[0801] Triethylamine (471 μl, 3.37 mmol) and formaldehyde (37% w/wsolution. 273 mg, 3.37 mmol) were added to a suspension of the aminefrom preparation 159 (641 mg, 1.69 mmol) in acetonitrile (10 ml), andthe solution stirred at room temperature for 1 hour. Sodiumtriacetoxyborohydride (1.79 g, 3.37 mmol) was then added and thereaction stirred at room temperature for 18 hours. The mixture wasneutralised using saturated sodium bicarbonate solution, then extractedusing dichloromethane (3×50 ml). The combined organic solutions weredried over magnesium sulphate and evaporated under reduced pressure. Thecrude product was purified by column chromatography on silica gel usingan elution gradient of dichloromethane: methanol: 0.88 ammonia (93:7:0.2to 91:9:0.6) to afford the title compound as an orange solid (342 mg).

[0802]¹H-nmr (CDCl₃, 400 MHz) δ: 1.80-2.00 (m, 4H), 2.15 (m, 2H), 2.36(s, 3H), 2.67 (m, 1H), 2.84 (t, 2H), 3.00 (m, 4H), 3.58 (s, 2H), 3.69(s, 2H), 6.93 (d, 1H), 7.28 (m, 6H).

[0803] LRMS: m/z (ES⁺) 322 [MH⁺)

Preparation 161 1-tert-Butyl 2-ethyl(2R,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate

[0804]

[0805] Triethylamine (0.27 ml, 2.05 mmol) followed by di-tert-butyldicarbonate (223 mg, 1.02 mmol) were added to a solution of ethyl(2R,4R)-4-hydroxy-2-pyrrolidinecarboxylate hydrochloride (J. Org. Chem.1990; 1684) (200 mg, 1.02 mmol) in 1,4-dioxane (5 ml) and water (5 ml),and the reaction stirred at room temperature for 4 hours. The mixturewas extracted with ethyl acetate (50 ml), and the organic solutionwashed sequentially with 0.25M hydrochloric acid (50 ml), water (50 ml)and brine (50 ml). The solution was then dried over magnesium sulphateand evaporated under reduced pressure to afford the title compound (110mg).

[0806]¹H-nmr (CDCl₃, 400 MHz) δ: 1.24 (t, 3H), 1.42 (s, 9H), 2.20 (m,2H), 3.52 (m, 2H), 4.23 (q, 2H), 4.35 (m, 2H).

[0807] LRMS: m/z (ES⁺) 282 [MNa⁺]

Preparation 162 tert-Butyl(2R,4R)-4-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate

[0808]

[0809] Lithium borohydride (1.4 ml, 2M in tetrahydrofuran, 2.8 mmol) wasadded dropwise to an ice-cooled solution of the ester from preparation161 (210 mg, 0.81 mmol) in tetrahydrofuran (10 ml), the solution stirredfor an hour at 0° C., and a further hour at room temperature. Thesolution was re-cooled to 0° C., water carefully added, followed by 2Nhydrochloric acid. The mixture was then warmed to room temperature andextracted with ethyl acetate (3×100 ml). The combined organic solutionswere washed with 1N sodium hydroxide solution, brine (100 ml), thendried over magnesium sulphate and evaporated under reduced pressure toafford the title compound (100 mg).

[0810]¹H-nmr (CDCl₃, 400 MHz) δ: 1.39 (s, 9H), 1.80 (m, 1H), 2.25 (m,1H), 3.36 (m, 3H), 3.98 (dd, 2H), 4.23 (m,1H).

[0811] LRMS: m/z (ES⁻) 216 [M−H⁻]

Preparation 163 tert-Butyl(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate

[0812]

[0813] Diisopropyl azodicarboxylate (0.5 ml, 2.53 mmol) was addeddropwise to an ice-cooled solution of the diol from preparation 162 (500mg, 2.30 mmol) and triphenylphosphine (664 mg, 2.53 mmol) indichloromethane (50 ml). Once addition was complete, the reaction wasstirred at room temperature for 18 hours. The mixture was partitionedbetween dichloromethane (100 ml) and water (100 ml), and the layersseparated. The aqueous phase was extracted with further dichloromethane(100 ml), and the combined organic solutions dried over magnesiumsulphate and evaporated under reduced pressure. The residue wastriturated with cyclohexane, the precipitate filtered, and the filtrateevaporated under reduced pressure. This product was purified by columnchromatography on silica gel using an elution gradient ofdichloromethane: methanol (100:0 to 91:9) to afford the title compound(200 mg).

[0814]¹H-nmr (CDCl₃, 400 MHz) δ: 1.43 (s, 9H), 1.82 (m, 2H), 3.29 (m,2H), 3.83 (m, 2H), 4.48 (m, 2H).

[0815] LRMS: m/z (ES⁺) 222 [MNa⁺]

Preparation 164 (1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptane hydrochloride

[0816]

[0817] An ice-cooled solution of the compound from preparation 163 (200mg, 1.0 mmol) in dichloromethane (10 ml) was saturated with hydrogenchloride, and the solution then stirred at room temperature for 1 hour.The mixture was concentrated under reduced pressure and the residueazeotroped with diethyl ether to afford the title compound.

[0818]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.83 (d, 1H), 1.91 (d, 1H), 3.10 (s,2H), 3.64 (d, 1H), 3.92 (d, 1H), 4.35 (s, 1H), 4.61 (s, 1H), 9.22 (s,2H)

Preparation 165(1R,4R)-5-[(6-benzyl-5,6,7,8-tetrahydro[2,6]naphthyridin-1-yl)methyl]-2-oxa-5-azabicyclo[2.2.1]heptane

[0819]

[0820] Sodium triacetoxyborohydride (418 mg, 1.98 mmol) was added to asolution of the aldehyde from preparation 35 (211 mg, 1.25 mmol), theamine hydrochloride from preparation 164 (170 mg, 1.25 mmol), sodiumacetate (72 mg, 0.88 mmol), and acetic acid (50 μl, 8.7 mmol) intetrahydrofuran (10 ml), and the reaction was stirred at roomtemperature for 4 hours. The solution was diluted with water (15 ml) and0.88 ammonia (15 ml), and the mixture then extracted with ethyl acetate.The organic extract was washed with brine, dried over magnesium sulphateand concentrated under reduced pressure. The residual oil was purifiedby column chromatography on silica gel using dichloromethane: methanol(100:0 to 92.5:7.5) to afford the title compound as a yellow oil, 127mg.

[0821]¹H-nmr (CDCl₃, 400 MHz) δ: 1.70 (dd, 1H), 1.94 (dd, 1H), 2.65 (d,1H), 2.79 (t, 2H), 2.92 (dd, 1H), 2.99 (t, 2H), 3.42 (m, 1H), 3.60 (m,3H), 3.70 (s, 2H), 3.81 (dd, 2H), 4.08 (d, 1H), 4.39 (s, 1H), 6.81 (d,1H), 7.32 (m, 5H), 8.24 (d, 1H).

[0822] LRMS: m/z (ES⁺) 336 [MH⁺]

Preparation 1662-Benzyl-5-(3-methoxy-azetidin-1-ylmethyl)-1,2,3,4-tetrahydro-[2,6]naphthyridine

[0823]

[0824] N,N-Diisopropylethylamine (517 mg, 4 mmol) was added to asolution of the amine hydrochloride from preparation 21 (494 mg, 4 mmol)and the aldehyde from preparation 35 (756 mg, 3 mmol) in tetrahydrofuran(20 ml), and the solution was stirred for 10 minutes. Acetic acid (480mg, 8 mmol) was then added, followed by sodium triacetoxyborohydride(2.12 g, 10 mmol) and the reaction mixture was stirred at roomtemperature for 45 minutes. 2M Hydrochloric acid (5 ml) was added, themixture then re-basified using 1N sodium hydroxide solution, and themixture extracted with dichloromethane (3×50 ml). The combined organicsolutions were dried over magnesium sulphate and evaporated underreduced pressure to give the final compound as a yellow oil (970 mg).

[0825]¹H-nmr (CDCl₃, 400 MHz) δ: 2.78 (m, 2H), 2.86 (m, 2H), 3.03 (m,4H), 3.22 (s, 3H), 3.58 (s, 2H), 3.67 (m, 4H), 4.03 (m, 1H), 6.78 (d,1H), 7.25 (m, 1H), 7.34 (m, 4H), 8.23 (d, 1H).

[0826] LRMS: m/z (ES⁺) 324 [MH⁺]

Preparation 167 tert-Butyl (3S)-3-methoxy-1-pyrrolidinecarboxylate

[0827]

[0828] Sodium hydride (2.2 g, 80% dispersion in mineral oil, 73.2 mmol)was added to an ice-cooled solution of(3S)-N-tert-butoxycarbonylpyrrolidin-3-ol (U.S. Pat. No. 6,180,627preparation 78), (12.5 g, 66.7 mmol) in tetrahydrofuran (330 ml), andthe solution was stirred at room temperature for an hour. Iodomethane(14.5 g, 100 mmol) was then added and the reaction stirred for 18 hours.Water (100 ml) was added and the mixture concentrated under reducedpressure to remove the organic solvents. The solution was partitionedbetween water (750 ml) and ethyl acetate (750 ml) the layers separated,and the organic solution dried over magnesium sulphate and evaporatedunder reduced pressure to give the title compound.

[0829]¹Hnmr (CDCl₃, 400 MHz) δ: 1.42 (s, 9H), 1.84-2.00 (m, 2H), 3.32(s, 3H), 3.40 (m, 4H), 3.92 (m, 1H).

Preparation 168 (3S)-3-Methoxypyrrolidine trifluoroacetate

[0830]

[0831] Hydrogen chloride was bubbled through an ice-cooled solution ofthe protected amine from preparation 167 (23.77 g, 118 mmol) in diethylether(591 ml), until saturated, and the solution was stirred for 1 hourat room temperature. The reaction was concentrated under reducedpressure and the residue re-suspended in diethyl ether. The mixture wasstirred for 3 hours and the ether decanted off, the residue wasevaporated under reduced pressure. The product was dissolved in ethanol,trifluoroacetic acid (16 ml) added, and the solution evaporated underreduced pressure to afford the title compound.

[0832]¹Hnmr (CDCl₃, 400 MHz) δ: 2.00 (m, 1H), 2.18 (m, 1H), 3.25-3.48(m, 7H), 4.06 (m, 1H), 8.75 (s, 1H), 9.24 (s, 1H).

Preparation 1692-Benzyl-5-{[(3S)-3-methoxypyrrolidinyl]methyl}-1,2,3,4-tetrahydro[2,6]naphthyridine

[0833]

[0834] A solution of the aldehyde from preparation 35 (500 mg, 2 mmol)and the pyrrolidine from preparation 168 (385 mg, 2.8 mmol) indichloromethane (10 ml) was stirred at room temperature for 30 minutes.Sodium triacetoxyborohydride (1.05 g, 5 mmol) was added and the reactionstirred at room temperature for 18 hours. The reaction was washed withsodium bicarbonate solution, and this aqueous solution extracted withfurther dichloromethane (2×). The combined organic solutions were driedover magnesium sulphate and evaporated under reduced pressure. Theresidual oil was purified by column chromatography on silica gel usingan elution gradient of dichloromethane: methanol: 0.88 ammonia (98:2:0.2to 90:10:1) to afford the title compound as an orange oil (290 mg).

[0835]¹H-nmr (CDCl₃, 400 MHz) δ: 1.82 (m, 1H), 2.13 (m, 1H), 2.60-2.82(m, 5H), 3.00 (m, 3H), 3.27 (s, 3H), 3.60 (s, 2H), 3.70 (s, 2H), 3.80(m, 2H), 3.97 (m, 1H), 6.81 (d, 1H), 7.22-7.40 (m, 5H), 8.24 (d, 1H).

[0836] LRMS: m/z (ES⁺) 360 [MNa⁺]

Preparation 1707-Benzyl-3-(4-morpholinyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

[0837]

[0838] A mixture of the bromide from preparation 83 (292 mg, 1 mmol) andtetrakis(triphenylphosphine) palladium (0) (23 mg, 0.22 mmol) inmorpholine (2 ml) was heated under reflux for 20 hours. The cooledmixture was poured into 0.1N sodium hydroxide solution and extractedwith dichloromethane (3×50 ml). The combined organic extracts were driedover magnesium sulphate and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel using anelution gradient of ethyl acetate: methanol (100:0 to 93:7) to affordthe title compound as a yellow oil (182 mg).

[0839]¹H-nmr (CDCl₃, 400 MHz) δ: 2.80 (t, 2H), 3.07 (m, 4H), 3.62 (s,2H), 3.68 (s, 2H), 3.81 (m, 6H), 6.49 (s, 1H), 7.32 (m, 5H).

[0840] LRMS: m/z (ES⁺) 321 [MNa⁺]

Preparation 171 (7-Benzyl-5,67,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)(cyclopropyl)methanol

[0841]

[0842] n-Butyl lithium (4.97 ml, 7.95 mmol) was added dropwise to acooled (−78° C.) solution of the bromide from preparation 83 (1.60 g,7.50 mmol) in tetrahydrofuran (16 ml), so as to maintain the temperaturebelow −70° C., and once addition was complete, the solution was allowedto warm to 0° C. slowly. Cyclopropanecarboxaldehyde (1.68 ml, 22.5 mmol)was then added, the solution stirred for a further 20 minutes at 0° C.,then quenched by the addition of water (10 ml). The mixture wasneutralised using 2N hydrochloric acid, then extracted with ethylacetate (3×50 ml) and methanol: dichloromethane (5:95, 3×50 ml). Thecombined organic solutions were dried over magnesium sulphate andconcentrated under reduced pressure. The residual oil was purified bycolumn chromatography on silica gel using an elution gradient ofdichloromethane: methanol (100:0 to 95:5) to afford the title compoundas an orange solid (1.18 g).

[0843]¹H-nmr (CDCl₃, 400 MHz) δ: 0.40 (m, 1H), 0.46 (m, 1H), 0.62 (m,2H), 1.42 (m, 1H), 2.17 (s, 1H), 2.83 (t, 2H), 3.65 (s, 2H), 3.69 (s,2H), 4.07 (m, 3H), 6.67 (s, 1H), 7.25-7.35 (m, 5H).

[0844] LRMS: m/z (ES⁺) 306 [MNa⁺]

Preparation 172(7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)(cyclopropyl)methylacetate

[0845]

[0846] 4-Dimethylaminopyridine (40.4 mg, 0.33 mmol), triethylamine (740μl, 5.30 mmol) and acetic anhydride (499 μl, 5.29 mmol) were added to asolution of the alcohol from preparation 171 (750 mg, 2.64 mmol) indichloromethane (20 ml), and the reaction stirred at room temperaturefor 18 hours. The solution was diluted with dichloromethane (30 ml),then washed with water (10 ml), saturated sodium bicarbonate solution(10 ml), dried over magnesium sulphate and evaporated under reducedpressure. The residual brown oil was purified by column chromatographyon silica gel using an elution gradient of dichloromethane: methanol(100:0 to 95:5) to afford the title compound as an orange oil (492 mg).

[0847]¹H-nmr (CDCl₃, 400 MHz) δ; 0.37 (m, 1H), 0.50 (m, 1H), 0.65 (m,2H), 1.72 (m, 1H), 2.07 (s, 3H), 2.82 (t, 2H), 3.64 (s, 2H), 3.68 (s,2H), 3.94 (m, 1H), 4.02 (m, 1H) 5.21 (d, 1H), 6.75 (s, 1H), 7.31 (m,5H).

[0848] LRMS: m/z (ES⁺) 348 [MNa⁺]

Preparation 1733-Morpholin-4-ylmethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine

[0849]

[0850] The title compound was obtained from the benzyl compound frompreparation 139 (650 mg, 2.1 mmol) in 96% yield following the proceduredescribed in preparation 109.

[0851]¹H-nmr (CDCl₃, 400 MHz) δ: 2.45 (m, 4H), 3.21 (t, 2H), 3.58 (m,2H), 3.67 (m, 4H), 4.02 (t, 2H) 4.06 (s, 2H), 6.67 (s, 1H)

[0852] LRMS: m/z (ES⁺) 245 [MNa⁺]

Preparations 174 to 190

[0853] The compounds of the following tabulated preparations, wereprepared by a similar method to that of preparation 173 using theappropriate benzyl protected amine. Prep Structure Spectroscopic Data174

¹H-nmr(CDCl₃, 400MHz) δ: 3.00(s, 2H), 3.22(t, 2H), 4.01(m, 4H), 4.62(s,2H), 6.66(s, 1H) LRMS: m/z(ES⁺) 154[MH⁺] 175

¹H-nmr(CDCl₃, 400MHz) δ: 1.65(m, 3H), 2.03(m, 2H), 2.90(m, 2H), 3.15(t,2H), 3.26(m, 2H), 3.33(m, 1H), 3.39(s, 3H), 3.74(t, 2H), 4.01(s, 2H),6.50(s, 1H) LRMS: m/z (ES⁺) 237[MH⁺] 176

¹H-nmr(CDCl₃, 400MHz) δ: 2.28(s, 6H), 2.34(m, 2H), 2.53(t, 2H), 3.19(t,2H), 3.50(m, 2H), 3.85(s, 2H), 4.79(s, 1H), 6.25(d, 1H), 7.90(d, 1H)LRMS: m/z(ES⁺) 221[MH⁺] 177

LRMS: m/z ES⁺241[MH⁺] 178

¹H-nmr(CDCl₃, 400MHz) δ: 2.28(s, 3H), 2.66(t, 2H), 2.90(t, 2H), 3.17(t,2H), 3.30(s, 3H), 3.50(t, 2H), 3.66(s, 2H), 3.98(s, 2H), 6.81(d, 1H),8.27(d, 1H) LRMS: m/z ES⁺ 258[MNa⁺] 179

¹H-nmr(CDCl₃, 400MHz) δ: 2.29(t, 2H), 3.08(s, 6H), 3.12(t, 2H), 3.74(s,2H), 4.47(s, 2H) LRMS: m/z ES⁺194[MH⁺] 180

¹H-nmr(CDCl₃, 400MHz) δ: 2.25(t, 2H), 3.10(m, 8H), 3.38(s, 3H), 3.57(t,2H), 3.66(q, 2H), 3.73(s, 2H), 4.68(t, 1H) LRMS: m/z ES⁺ 252[MH⁺] 181

¹H-nmr(CDCl₃, 400MHz) δ: 2.80(t, 2H), 3.20(t, 2H), 3.89(s, 2H), 4.60(d,2H), 5.40(s, 1H), 6.29(d, 1H), 7.07(d, 1H), 7.15(m, 1H), 7.25(d, 1H),7.61 (m, 1H), 8.55(d, 1H) LRMS: m/z ES⁺ 241.3[MH⁺] 182

¹H-nmr(ODCl₃, 400MHz) δ: 1.47(s, 9H), 1.60(s, 1H), 2.91(t, 2H), 3.20(t,2H), 3.97(s, 2H), 4.35(d, 2H), 5.41(s, 1H), 7.02(d, 1H), 7.26(s, 1H)LRMS: m/z ES⁺ 286[MNa⁺] 183

¹H-nmr(DMSOd₆, 400MHz) δ: 2.58(t, 2H), 2.73(t, 2H), 3.00(t, 2H), 3.45(t,2H), 3.70(s, 2H), 3.83(s, 2H), 7.13(d, 1H), 7.33(d, 1H). LRMS: m/z(ES⁺)208[MH⁺] 184

LRMS: m/z(ES⁺) 258[MNa⁺] 185

¹H-nmr(CD₃OD, 400MHz) δ: 2.04(m, 4H), 2.70(s, 3H), 2.77-2.96(m, 3H),3.04(m, 2H), 3.37 (m, 4H), 4.15(s, 2H), 7.18(d, 1H), 7.53(d, 1H). LRMS:m/z(ES⁺) 232[MH⁺] 186

LRMS: m/z(ES⁺) 258[MNa⁺] 187

¹H-nmr(CDCl₃, 400MHz) δ: 2.78(m, 2H), 3.03(m, 2H), 3.17(t, 2H), 3.21(s,3H), 3.63(m, 2H), 3.72(s, 2H), 3.96(s, 2H), 4.02(m, 1H), 6.80(d, 1H),8.24(d, 1H). LRMS: m/z (ES⁺) 234[MH⁺] 188

¹H-nmr(CDCl₃, 400MHz) δ: 1.80(m, 1H), 2.10(m, 1H), 2.45(s, 1H), 2.63(dd, 1H), 2.74(m, 2H), 2.94(m, 2H), 2.98(dd, 1H), 3.20 (t, 2H), 3.26(s,3H), 3.79(s, 2H), 3.96(m, 1H), 4.01(s, 2H), 6.84(d, 1H), 8.28(d, 1H).LRMS: m/z (ES⁺) 248[MH⁺] 189

¹H-nmr(CDCl₃, 400MHz) δ: 3.08(m, 4H), 3.18(t, 2H), 3.77(m, 2H), 3.80 (m,4H), 4.02(s, 2H), 6.52(s, 1H). LRMS: m/z(ES⁺) 231[MNa⁺] 190

¹H-nmr(CD₃OD, 400MHz) δ: 0.38-0.84(m, 4H), 1.30 (m, 1H), 3.46(s, 2H),3.80(m, 2H), 4.60(m, 4H), 7.58(s, 1H). LRMS: m/z(ES⁺) 178[MH⁺]

Preparation 191Methoxy-ethyl)-(5,6,7,8-tetrahydro-[1,6]naphthyridin-2-yl)-aminehydrochloride

[0854]

[0855] 10% Palladium on activated carbon (800 mg) was added to asolution of the N-benzyl compound from preparation 148 (1.31 g, 4.4mmol) and ammonium formate (1.39 g, 22 mmol) in methanol (50 ml). Themixture was heated under reflux for 1 hour, cooled to room temperatureand then filtered through Arbocel®. The filter cake was washed withdichloromethane/methanol (50:50, 400 ml) and the combined filtrates wereevaporated under reduced pressure. The residue was purified bychromatography on silica gel using methanol and ammonium hydroxide indichloromethane as eluant (gradient from 3:0.5:97 to 10:1:90). Thematerial isolated was azeotroped with dichloromethane and dried undervacuum. The residue was dissolved in dichloromethane (5 ml) and hydrogenchloride (1M in diethyl ether) was added. The solid formed was isolatedby filtration and was dried at 60° C. under vacuum to give the titlecompound as a pale yellow solid (832 mg).

[0856] LRMS: m/z ES⁺ 208.3 [MH⁺]

Preparation 1922-Methanesulfonyloxymethyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylicacid

[0857]

[0858] Methane sulphonyl chloride (140 μl, 1.8 mmol) was added to asolution of the alcohol from preparation 37 (400 mg, 1.5 mmol) andtriethylamine (229 μl, 1.6 mmol) in tetrahydrofuran (10 ml) at 0° C. Themixture was warmed to room temperature and was stirred for 3 hours. Thesolvent was evaporated under reduced pressure and the residue wasredissolved in tetrahydrofuran (10 ml) and partitioned between water (50ml) and dichloromethane (50 ml). The organic layer was separated, driedover magnesium sulphate and evaporated under reduced pressure to givethe title compound as an oil (622 mg).

[0859]¹H-nmr (CDCl₃, 400 MHz) δ: 1.42 (s, 9H), 2.96 (m, 2H), 3.75 (m,4H), 4.59 (s, 3H), 4.68 (s, 2H), 8.48 (s, 1H)

[0860] LRMS: m/z (ES⁺) 366 [MNa⁺]

Preparation 1932-Morpholin-4-ylmethyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylicacid tert-butyl ester

[0861]

[0862] The mesylate from preparation 192 (300 mg, 0.88 mmol) wasdissolved in morpholine (5 ml) containing N,N-diisopropylethylamine (150μl, 0.88 mmol) and the mixture was stirred at room temperature for 16hours. The reaction mixture was partitioned between dichloromethane (50ml) and water (50 ml) and the organic layers were dried over magnesiumsulphate and evaporated under reduced pressure. The residue was purifiedby chromatography on silica gel using methanol and ammonium hydroxide indichloromethane as eluant (gradient from 2:0.2:98 to 5:0.5:95) to givethe title compound as a yellow oil (260 mg).

[0863]¹H-nmr (CDCl₃, 400 MHz) δ: 1.50 (s, 9H), 2.59 (m, 4H), 2.96 (m,2H), 3.74 (m, 8H), 4.58 (s, 2H), 8.45 (s, 1H)

[0864] LRMS: m/z (ES⁺) 357 (MNa⁺]

Preparation 194 tert-Butyl5-{[(3R)-1-benzylpyrrolidinyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0865]

[0866] A solution of diethylazodicarboxylate (731 mg, 4.2 mmol) indichloromethane (5 ml) was added to an ice-cooled solution of thealcohol from preparation 22 (498 mg, 2 mmol) and triphenylphosphine(1.18 g, 4.5 mmol) in dichloromethane (35 ml), and the solution stirredfor 30 minutes. (S)-1-Benzyl-3-pyrrolidinol (885 mg, 5 mmol) was added,the mixture allowed to warm to room temperature and the reaction stirredfor a further 72 hours. The mixture was diluted with dichloromethane (50ml), washed with water (2×50 ml), dried over magnesium sulphate andconcentrated under reduced pressure. The residual oil was purified bycolumn chromatography on silica gel twice, using an elution gradient ofcyclohexane: propan-2-ol: 0.88 ammonia (95:6:0.2 to 90:10:0.4). Theproduct was azeotroped with methanol to afford the title compound as acolourless oil, 718 mg.

[0867]¹H-nmr (CDCl₃, 400 MHz) δ: 1.48 (s, 9H), 1.97 (m, 1H), 2.27 (m,1H), 2.65 (m, 3H), 2.75 (t, 2H), 3.03 (dd, 1H), 3.61 (t, 2H), 3.66 (dd,2H), 4.53 (s, 2H), 4.80 (m, 1H), 6.56 (d, 1H), 6.68 (d, 1H), 7.07 (dd,1H), 7.22-7.37 (m, 5H).

[0868] LRMS: m/z (ES⁺) 431 [MNa⁺]

Preparation 196 tert-Butyl5-{[(3S)-1-benzylpyrrolidinyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0869]

[0870] The title compound was obtained as a colourless oil in 82% yieldfrom (R)-1-benzyl-3-pyrrolidinol and the alcohol from preparation 22,according to the method described in preparation 194.

[0871]¹H-nmr (CDCl₃, 400 MHz) δ: 1.48 (s, 9H), 1.97 (m, 1H), 2.27 (m,1H), 2.65 (m, 3H), 2.75 (t, 2H), 3.05 (dd, 1H), 3.62 (t, 2H), 3.66 (dd,2H), 4.54 (s, 2H), 4.80 (m, 1H), 6.57 (d, 1H), 6.65 (d, 1H), 7.07 (dd,1H), 7.22-7.37 (m, 5H).

[0872] LRMS: m/z (ES⁺) 431 [MNa⁺]

Preparation 196 tert-Butyl5-({(2S)-1-[(benzyloxy)carbonyl]pyrrolidinyl}methoxy)-3,4-dihydro-2(1H)-isoguinolinecarboxylate

[0873]

[0874] The title compound was obtained as a colourless oil in 79% yieldfrom the alcohol from preparation 22 and benzyl(2S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (J. Chem. Soc. PerkinTrans. 1; EN; 19; 1997; 2891) (823 mg, 2.53mol), following a similarprocedure to that described in preparation 195, except cyclohexane:ethyl acetate (91:9 to 75:25) was used as the elution gradient.

[0875]¹H-nmr (CDCl₃, 400 MHz) δ: 1.46 (s, 9H), 1.88 (m, 1H), 2.05 (m,3H), 2.70 (m, 2H), 3.48 (m, 2H), 3.60 (m, 3H), 4.00 (m, 2H), 4.53 (m,2H), 5.14 (m, 2H), 6.65 (m, 2H), 7.09 (m, 1H), 7.33 (m, 5H).

[0876] LRMS: m/z (ES⁺) 490 [MNa⁺]

Preparation 197 tert-Butyl5-({(2R)-1-[(benzyloxy)carbonyl]pyrrolidinyl}methoxy)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0877]

[0878] The title compound was obtained as a colourless oil in 83% yieldfrom the alcohol from preparation 22 and benzyl(2R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (Tet. Lett. 33; 52;1992; 8011), following a similar procedure to that described inpreparation 195.

[0879]¹H-nmr (DMSOd₆ 400 MHz) δ: 1.39 (s, 9H), 1.80 (m, 1H), 2.00 (m,3H), 2.58 (m, 2H), 3.38 (m, 2H), 3.50 (m, 2H), 3.90-4.10 (m, 3H), 4.22(s, 2H), 5.05 (s, 2H), 6.65-7.10 (m, 3H), 7.26 (m, 5H).

[0880] LRMS: m/z (ES⁺) 489 [MNa⁺]

Preparation 198 tert-Butyl5-[(3R)-pyrrolidinyloxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0881]

[0882] A solution of the compound from preparation 195 (662 mg, 1.62mmol) in methanol (60 ml) was purged with argon, then heated underreflux, and allowed to cool slightly. 10% Palladium on carbon (330 mg)and ammonium formate (204 mg, 3.25 mmol) were added, and the mixtureheated at reflux for 10 minutes, then cooled rapidly to roomtemperature. The mixture was filtered through Arbocel®, washing throughwith ethanol, and the combined filtrate evaporated under reducedpressure. The residual oil was purified by column chromatography onsilica gel using an elution gradient of dichloromethane: methanol: 0.88ammonia (95:5:0.5 to 93:7:0.7) to afford the title compound as acolourless oil, 420 mg.

[0883]¹H-nmr (CDCl₃, 400 MHz) δ: 1.47 (s, 9H), 1.67 (s, 2H), 1.96 (m,1H), 2.06 (m, 1H), 2.70 (t, 2H), 2.91 (m, 1H), 3.04 (dd, 1H), 3.15 (m,1H), 3.61 (t, 2H), 4.53 (s, 2H), 4.81 (m, 1H), 6.64 (d, 1H), 6.69 (d,1H), 7.10 (dd, 1H).

[0884] LRMS: m/z (ES⁺) 319 [MH⁺]

Preparation 199 tert-Butyl5-[(3S)-pyrrolidinyloxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0885]

[0886] The title compound was obtained as a colourless oil in 89% yieldfrom the compound from preparation 196, following the proceduredescribed in preparation 198.

[0887]¹H-nmr (CDCl₃, 400 MHz) δ: 1.47 (s, 9H), 1.67 (s, 2H), 1.96 (m,1H), 2.06 (m, 1H), 2.70 (t, 2H), 2.90 (m, 1H), 3.04 (dd, 1H), 3.15 (m,1H), 3.62 (t, 2H), 4.53 (s, 2H), 4.81 (m, 1H), 6.64 (d, 1H), 6.69 (d,1H), 7.10 (dd, 1H).

[0888] LRMS: m/z (ES⁺) 319 [MH⁺]

Preparation 200 tert-Butyl5-[(2S)-pyrrolidinylmethoxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0889]

[0890] The title compound was obtained as a colourless oil in 90% yieldfrom the compound from preparation 196, following the proceduredescribed in preparation 198.

[0891]¹H-nmr (CDCl₃, 400 MHz) δ: 1.47 (s, 9H), 1.60 (m, 1H), 1.66 (m,1H), 1.80 (m, 2H), 1.95 (m, 1H), 2.75 (t, 2H), 2.94 (m, 1H), 3.02 (m,1H), 3.52 (m, 1H), 3.61 (t, 2H), 3.90 (m, 2H), 4.54 (s, 2H), 6.70 (m,2H), 7.10 (dd, 1H).

[0892] LRMS: m/z (ES⁺) 333 [MH⁺]

Preparation 201 tert-Butyl5-[(2R)-pyrrolidinylmethoxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0893]

[0894] The title compound was obtained as a colourless oil in 87% yieldfrom the compound from preparation 197, following the proceduredescribed in preparation 198.

[0895]¹H-nmr (CDCl₃, 400 MHz) δ: 1.47 (s, 9H), 1.60 (m, 1H), 1.66 (m,1H), 1.80 (m, 2H), 1.95 (m, 1H), 2.75 (t, 2H), 2.94 (m, 1H), 3.02 (m,1H), 3.52 (m, 1H), 3.61 (t, 2H), 3.90 (m, 2H), 4.54 (s, 2H), 6.69 (m,2H), 7.10 (dd, 1H).

[0896] LRMS: m/z (ES⁺) 333 [MH⁺]

Preparation 202 tert-Butyl5-{[(3R)-1-methylpyrrolidinyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0897]

[0898] Acetic acid (156 mg, 2.6 mmol) was added dropwise to a solutionof the pyrrolidine from preparation 198 (395 mg, 1.24 mmol) intetrahydrofuran (10 ml), followed by formaldehyde (210 μl, 37%, 2.6mmol), and the solution stirred for 20 minutes. Sodiumtriacetoxyborohydride (788 mg, 3.72 mmol) was added, and the reactionstirred at room temperature for 72 hours. The mixture was partitionedbetween dichloromethane (75 ml) and water (75 ml), and the layersseparated. The aqueous phase was basified using 10% aqueous sodiumcarbonate solution and extracted with further dichloromethane (2×50 ml).The combined organic solutions were dried over magnesium sulphate andevaporated under reduced pressure. The residual oil was purified bycolumn chromatography on silica gel using an elution gradient ofdichloromethane: methanol: 0.88 ammonia (97:3:0.2 to 93:7:0.7), thenazeotroped with methanol to afford the title compound as a pale yellowoil (378 mg).

[0899]¹H-nmr (CDCl₃, 400 MHz) δ: 1.47 (s, 9H), 1.98 (m, 1H), 2.29 (m,1H), 2.38 (s, 3H), 2.52 (m, 1H), 2.74 (m, 4H), 2.91 (m, 1H), 3.59 (dd,2H), 4.53 (s, 2H), 4.80 (m, 1H), 6.57 (d, 1H), 6.68 (d, 1H), 7.09 (dd,1H).

[0900] LRMS: m/z (ES⁺) 333 [MH⁺]

Preparation 203 tert-Butyl5-{[(3S)-1-methylpyrrolidinyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0901]

[0902] The title compound was obtained as a pale yellow oil in 94% yieldfrom the compound from preparation 199 and formaldehyde following theprocedure described in preparation 202.

[0903]¹H-nmr (CDCl₃, 400 MHz) δ: 1.47 (s, 9H), 1.98 (m, 1H), 2.29 (m,1H), 2.38 (s, 3H), 2.52 (m, 1H), 2.74 (m, 4H), 2.91 (m, 1H), 3.59 (dd,2H), 4.53 (s, 2H), 4.80 (m, 1H), 6.57 (d, 1H), 6.68 (d, 1H), 7.09 (dd,1H).

[0904] LRMS: m/z (ES⁺) 333 [MH⁺]

Preparation 204 tert-Butyl5-{[(2S)-1-methylpyrrolidinyl]methoxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0905]

[0906] The title compound was obtained as a pale yellow oil in 94% yieldfrom the pyrrolidine from preparation 200 and formaldehyde, followingthe procedure described in preparation 202.

[0907]¹H-nmr (CDCl₃, 400 MHz) δ: 1.47 (s, 9H), 1.68 (m, 1H), 1.79 (m,2H), 2.03 (m, 1H), 2.30 (m, 1H), 2.48 (s, 3H), 2.66 (m, 1H), 2.74 (m,2H), 3.09 (m, 1H), 3.60 (m, 2H), 3.84 (m, 1H), 3.98 (m, 1H), 4.54 (s,2H), 6.68 (m, 2H), 7.10 (dd, 1H).

[0908] LRMS: m/z (ES⁺) 347 [MH⁺]

Preparation 204 tert-Butyl5-{[(2S)-1-methylpyrrolidinyl]methoxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0909]

[0910] The title compound was obtained as a pale yellow oil in 90% yieldfrom the pyrrolidine from preparation 201 and formaldehyde, followingthe procedure described in preparation 202.

[0911]¹H-nmr (CDCl₃, 400 MHz) δ: 1.47 (s, 9H), 1.68 (m, 1H), 1.79 (m,2H), 2.03 (m, 1H), 2.30 (m, 1H), 2.48 (s, 3H), 2.66 (m, 1H), 2.74 (m,2H), 3.09 (m, 1H), 3.60 (m, 2H), 3.84 (m, 1H), 3.98 (m, 1H), 4.54 (s,2H), 6.68 (m, 2H), 7.10 (dd, 1H).

[0912] LRMS: m/z (ES⁺) 347 [MH⁺]

Preparation 205 tert-Butyl2-formyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0913]

[0914] A solution of dimethylsulphoxide (1.41 ml, 19.9 mmol) indichloromethane (2 ml) was added to a cooled (−65° C.) solution oftrifluoroacetic anhydride (2.08 ml, 14.9 mmol) in dichloromethane (40ml), and the solution stirred for 30 minutes. A solution of the alcoholfrom preparation 37 (2.5 g, 9.96 mmol) in dichloromethane (10 ml) wasadded dropwise, so as to maintain the temperature below −60° C., andonce addition was complete, the solution was stirred for a further 30minutes. Triethylamine (6.94 ml, 49.8 mmol) was slowly added, thereaction stirred for a further hour at −65° C., and then poured intoethyl acetate (200 ml) and water (100 ml). The phases were separated,the organic phase washed with water (150 ml), 10% aqueous citric acidsolution (150 ml) and brine (150 ml), then dried over magnesium sulphateand evaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel using ethyl acetate as eluant, toafford the title compound, 1.3 g.

[0915] LRMS: m/z (ES⁺) 286 [MNa⁺]

Preparation 206 tert-Butyl2-{[(2-methoxyethyl)amino]methyl}-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0916]

[0917] 2-Methoxyethylamine (0.21 ml, 2.45 mmol) and acetic acid (0.10ml, 1.79 mmol) were added to a solution of the aldehyde from preparation205 (430 mg, 1.63 mmol) in tetrahydrofuran (10 ml), and the solutionstirred at room temperature for 1 hour. Sodium triacetoxyborohydride(0.87 g, 4.08 mmol) was added and the reaction stirred at roomtemperature for 18 hours. The mixture was concentrated under reducedpressure and the residue partitioned between 0.88 ammonia and ethylacetate, and the layers separated. The organic phase was washed withbrine, dried over magnesium sulphate and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel using an elution gradient of dichloromethane: methanol (98:2to 95:5) to afford the title compound (282 mg).

[0918]¹H-nmr (CDCl₃, 400 MHz) δ: 1.48 (s, 9H), 2.86 (t, 2H), 2.92 (t,2H), 3.37 (s, 3H) 3.55 (t, 2H), 3.72 (t, 2H), 4.02 (s, 2H), 4.57 (s,2H), 8.41 (s, 1H).

Preparation 207 tert-Butyl2-({[(1S)-2-methoxy-1-methylethyl]amino}methyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0919]

[0920] The title compound was obtained, quantitatively from the aldehydefrom preparation 205 and (S)-(+)-1-methoxy-2-propylamine, following asimilar procedure to that described in preparation 206, except thecompound was isolated without column chromatography.

[0921]¹H-nmr (CDCl₃, 400 MHz) δ: 1.07 (d, 3H), 1.45 (s, 9H), 2.94 (m,2H), 3.35 (m, 6H), 3.74 (t, 2H), 3.96-4.10 (dd, 2H), 4.57 (s, 2H), 8.40(s, 1H).

[0922] LRMS: m/z (ES⁺) 359 [MNa⁺]

Preparation 208 tert-Butyl2-{[[(1S)-2-methoxy-1-methylethyl](methyl)amino]methyl}-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0923]

[0924] Formaldehyde (608 μl, 7.5 mmol), followed by sodiumtriacetoxyborohydride (2.12 g, 10 mmol) were added to a solution of theamine from preparation 207 (842 mg, 2.5 mmol) in dichloromethane (40ml), and the reaction was stirred at room temperature for 18 hours. Themixture was partitioned between dichloromethane (100 ml) and 0.88ammonia (100 ml), and the layers separated. The organic phase was washedwith brine (100 ml), dried over sodium sulphate and evaporated underreduced pressure. The crude product was purified by columnchromatography on silica gel using an elution gradient ofdichloromethane: methanol (100:0 to 97:3) to afford the title compound,523 mg.

[0925]¹H-nmr (CDCl₃, 400 MHz) δ: 1.08 (d, 3H), 1.46 (s, 9H), 2.38 (s,3H), 2.95 (m, 2H), 3.00 (m, 1H), 3.35 (s, 3H), 3.44 (s, 2H), 3.75 (m,2H), 3.85 (s, 2H), 4.58 (s, 2H).

[0926] LRMS: m/z (ES⁺) 373 [MNa⁺]

Preparation 209 tert-Butyl2-{[ethyl(2-methoxyethyl)amino]methyl}-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0927]

[0928] Acetaldehyde (0.21 ml, 3.8 mmol) was added to a solution of theamine from preparation 206 (282 mg, 0.97 mmol) in dichloromethane (10ml) and the solution stirred for 1 hour at room temperature. Sodiumtriacetoxyborohydride (1.03 g, 4.8 mmol) was added and the reaction wasstirred at room temperature for 18 hours. The mixture was concentratedunder reduced pressure and the residue partitioned between 0.88 ammonia(100 ml) and ethyl acetate (100 ml) and the layers separated. Theorganic phase was washed with brine (100 ml), dried over magnesiumsulphate and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel using an elutiongradient of dichloromethane: methanol (99:1 to 96:4) to afford the titlecompound, 90 mg.

[0929]¹H-nmr (CDCl₃, 400 MHz) δ: 1.08 (t, 3H), 1.48 (s, 9H), 2.72 (q,2H), 2.81 (t, 2H), 2.91 (t, 2H), 3.33 (s, 3H), 3.54 (t, 2H), 3.75 (t,2H), 3.92 (s, 2H), 4.57 (s, 2H), 8.44 (s, 1H).

[0930] LRMS: m/z (ES⁺) 373 [MNa⁺]

Preparation 210 tert-Butyl2-[(4-methoxy-1-piperidinyl)methyl]-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0931]

[0932] Triethylamine (305 μl, 2.19 mmol) and methanesulphonyl chloride(185 μl, 2.39 mmol) were added to a solution of the alcohol frompreparation 37 (500 mg, 1.99 mmol) in dichloromethane (5 ml), and thesolution stirred at room temperature for 3 hours. The mixture wasevaporated under reduced pressure and the residue re-dissolved intetrahydrofuran (5 ml) and 4-methoxypiperidine (J. Chem. Soc. 1984, (4),737, Example 13) (1 g, 5.98 mmol) added, and the reaction mixture wasstirred at room temperature for 18 hours. The mixture was partitionedbetween dichloromethane (30 ml) and water (30 ml), the layers separated,and the aqueous phase extracted with dichloromethane (30 ml). Thecombined organic solutions were dried over sodium sulphate andevaporated under reduced pressure to give a brown oil. This was purifiedby column chromatography on silica gel using an elution gradient ofdichloromethane: methanol: 0.88 ammonia (98:2:1 to 96:4:1) to afford thetitle compound as a yellow gum (350 mg).

[0933]¹H-nmr (CDCl₃, 400 MHz) δ: 1.49 (s, 9H), 1.68 (m, 2H), 1.89 (m,2H), 2.28 (m, 2H), 2.81 (m, 2H), 2.95 (t, 2H), 3.21 (m, 1H), 3.32 (s,3H), 3.73 (m, 4H), 4.57 (s, 2H), 8.45 (s, 1H).

[0934] LRMS: m/z (ES⁺) 363 [MH⁺]

Preparation 211(2-Methoxy-ethyl)-methyl-(5,6,7,8-tetrahydro-[1,6]naphthyridin-2-ylmethyl)-amine

[0935]

[0936] The title compound was obtained as a pale yellow oil from thebenzyl compound from preparation 156 (832 mg, 2.55 mmol) following theprocedure described in preparation 109.

[0937] LRMS: m/z (ES⁺) 258 [MNa⁺]

Preparation 2122-Morpholin-4-ylmethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinedihydrochloride

[0938]

[0939] The protected amine from preparation 210 (243 mg, 0.72 mmol) wasdissolved in dichloromethane (15 ml) at 0° C. and hydrogen chloride gaswas bubbled through the solution for 10 minutes. The solvent was removedunder reduced pressure to give the title compound as a white solid (200mg)

[0940]¹H-nmr (DMSOd₆ 400 MHz) δ: 2.48 (m, 4H), 3.13 (m, 2H), 3.49 (m,2H), 3.90 (m, 4H), 4.35 (s, 2H), 4.63 (s, 2H), 8.79 (s, 1H), 9.95 (s,2H)

[0941] LRMS: m/z (ES⁺) 235 [MH⁺]

Preparations 213 to 215

[0942] The compounds of the following tabulated preparations, of thegeneral formula

[0943] were prepared by a similar method to that of preparation 212using the appropriate protected amine. Prep Structure Spectroscopic Data213

¹H-nmr (CDCl₃, 400MHz) δ: 1.22(t, 3H), 2.46(m, 2H), 3.12(t, 2H), 3.22(s,3H), 3.42(m, 2H), 3.44(m, 2H), 3.68(t, 2H), 4.35(s, 2H), 4.60(s, 2H),8.75(s, 1H). LRMS: m/z(ES⁺) 251[MH⁺] 214

¹H-nmr(DMSOd₆, 400MHz) δ: 1.23(m, 3H), 2.82(s, 3H), 3.14(t, 2H), 3.24(m,3H), 3.46(m, 2H), 3.60(m, 2H), 3.77(m, 1H), 4.38(s, 2H), 4.50(m, 1H),4.64(m, 1H), 8.79(s, 1H), 10.07(m, 1H). LRMS: m/z(ES⁺) 251[MH⁺] 215

¹H-nmr(DMSOd₆, 400MHz) δ: 1.70(m, 1H), 1.98(m, 2H), 2.15(m, 1H),3.12-3.25(m, 8H), 3.38 (m, 2H), 3.47(m, 2H), 3.57(m, 2H), 4.35(s, 2H),4.60(s, 2H), 8.80(s, 1H). LRMS: m/z(ES⁺) 275[MNa⁺]

Preparation 2165-{[(3R)-1-Methylpyrrolidinyl]oxy}-1,2,3,4-tetrahydroisoquinoline

[0944]

[0945] Trifluoroacetic acid (5 ml) was added dropwise to a solution ofthe protected amine from preparation 202 (354 mg, 1.06 mmol) indichloromethane (5 ml), and the solution then stirred at roomtemperature for 3.5 hours. The reaction mixture was concentrated underreduced pressure and the residue azeotroped with toluene. The crudeproduct was purified by column chromatography on silica gel using anelution gradient of dichloromethane: methanol: 0.88 ammonia (97:3:0.2 to90:10:1) to afford the title compound as a colourless oil (220 mg).

[0946]¹H-nmr (CDCl₃, 400 MHz) δ: 1.98 (m, 2H), 2.28 (m, 1H), 2.38 (s,3H), 2.52 (m, 1H), 2.65 (t, 2H), 2.69 (m, 2H), 2.93 (m, 1H), 3.11 (t,2H), 3.96 (s, 2H), 4.80 (m, 1H), 6.55 (d, 1H), 6.60 (d, 1H), 7.04 (dd,1H).

[0947] LRMS: m/z (ES⁺) 233 [MH⁺]

Preparations 217 to 219

[0948] The compounds of the following tabulated preparations wereprepared by a similar method to that of preparation 216 from theappropriate protected amines. Prep Structure Spectroscopic Data 217

¹H-nmr(CDCl₃, 400MHz) δ: 1.98(m, 2H), 2.28(m, 1H), 2.38(s, 3H), 2.52(m,1H), 2.65(t, 2H), 2.69 (m, 2H), 2.93(m, 1H), 3.11(t, 2H), 3.96(s, 2H),4.80(m, 1H), 6.55(d, 1H), 6.60(d, 1H), 7.04(dd, 1H). LRMS: m/z(ES⁺)233[MH⁺] 218

¹H-nmr(CDCl₃, 400MHz) δ: 1.68(m, 1H), 1.80(m, 2H), 1.95(m, 1H), 2.03(m,1H), 2.30(dd, 1H), 2.50(s, 3H), 2.67(m, 3H), 3.11(m, 3H), 3.84(m, 1H),3.96(m, 3H), 6.63(m, 2H), 7.06(dd, 1H). LRMS: m/z(ES⁺) 247[MH⁺] 219

¹H-nmr(CDCl₃, 400MHz) δ: 1.68(m, 1H), 1.80(m, 2H), 2.01(m, 1H), 2.30(dd,1H), 2.49(s, 3H), 2.67 (m, 3H), 3.11(m, 3H), 3.84(m, 1H), 3.96(s, 2H),3.99(m, 1H), 6.63(m, 2H), 7.06(dd, 1H). LRMS: m/z(ES⁺) 247[MH⁺]

Preparation 220{tert-Butoxycarbonylimino-[2-(2-methoxy-ethylamino)-7,8-dihydro-5H-[1,6]naphthyridin-6-yl]-methyl}-carbamicacid tert-butyl ester

[0949]

[0950] Mercury (II) chloride (1.29 g, 4.78 mmol) was added to the aminefrom preparation 191 (0.9 g, 4.34 mmol), triethylamine (1.67 ml, 12mmol) and 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (1.39g, 4.78 mmol) in dichloromethane (25 ml) and the mixture was stirred atroom temperature for 16 hours. The reaction mixture was diluted withdichloromethane and filtered through Arbocel® and the filtrate wasevaporated under reduced pressure. The residue was purified bychromatography on silica gel using ethyl acetate in pentane as eluant(50:50) to give the title compound as a white solid (1.5 g).

[0951]¹H-nmr (CDCl₃, 400 MHz) δ: 1.50 (s, 18H), 2.93 (m, 2H), 3.36 (s,3H), 3.48 (m, 2H), 3.55 (m, 2H), 3.80 (m, 2H), 4.57 (s, 2H), 4.68 (d,1H), 6.24 (d, 1H), 7.11 (d, 1H), 10.08 (s, 1H)

[0952] LRMS: m/z (ES⁻) 448 [M−H]⁻

Preparations 221 to 223

[0953] The compounds of the following tabulated preparations, of thegeneral formula:

[0954] were prepared by a similar method to that of preparation 220using the appropriate amine. Prep R Spectroscopic Data 221

¹H-nmr(CDCl₃, 400MHz) δ: 1.50(s, 18H), 3.17(t, 2H), 3.85(t, 2H), 4.72(s,2H), 7.09 (m, 1H), 7.40(d, 1H), 8.43(d, 1H), 10.12(s, 1H) LRMS: m/z ES⁺399[MNa⁺] 222

¹H-nmr(CDCl₃, 400MHz) δ: 1.48(s, 18H), 2.61(m, 2H), 3.38(s, 3H), 3.59(m,2H), 3.67(m, 2H), 3.80(m, 2H), 4.50(s, 1H), 4.59(s, 2H), 6.33 (d, 1H),7.91(d, 1H), 10.17(s, 1H) LRMS: m/z ES⁺450[MH⁺] 223

¹H-nmr(CDCl₃, 400MHz) δ: 1.52(s, 18H), 2.74(s, 2H), 3.83(s, 2H), 4.60(s,2H), 4.79 (s, 2H), 5.57(s, 1H), 6.37(d, 1H), 7.17(m, 1H), 7.30(d, 1H),7.63(m, 1H), 7.96(s, 1H), 8.55(d, 1H), 10.18(s, 1H) LRMS: m/zES⁺505[MNa⁺]

Preparation 2242-(2-Methoxy-ethylamino)-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxamidinedihydrochloride

[0955]

[0956] Hydrogen chloride gas was bubbled into a solution of theprotected amidine from preparation 220 (1.5 g, 3.34 mmol) indichloromethane for 10 minutes. The mixture was stirred at roomtemperature for 1 hour. The solvent was evaporated under reducedpressure to give the title compound as a white solid (1 g).

[0957]¹H-nmr (DMSOd₆ 400 MHz) δ: 3.04 (m, 2H), 3.27 (s, 3H), 3.52 (t,2H), 3.63 (t, 2H), 3.74 (m, 2H), 4.51 (s, 2H), 7.01 (d, 1H), 7.60 (d,1H), 7.79 (s, 4H)

[0958] LRMS: m/z (ES⁺) 292 [MH]⁺

Preparations 225 to 227

[0959] The compounds of the following tabulated preparations, of thegeneral formula:

[0960] were prepared by a similar method to that of preparation 224using the appropriate amidine. Prep R Spectroscopic Data   225^(A)

¹H-nmr(DMSOd₆ 400MHz) δ: 3.01(t, 2H), 3.75(t, 2H), 4.64 (s, 2H), 7.45(s,5H), 7.59(d, 1H), 8.43(d, 1H) LRMS: m/z ES⁺ 177[MH⁺] 226

¹H-nmr(CD₃OD, 400MHz) δ: 2.78(m, 2H), 3.36(s, 3H), 3.68(m, 4H), 3.82(t,2H), 4.68 (s, 2H), 6.76(d, 1H), 6.73(d, 1H) LRMS: m/z ES⁺251[MH⁺] 227

¹H-nmr(CD₃OD, 400MHz) δ: 2.94(m, 2H), 3.88(m, 2H), 4.73(s, 2H), 5.20(s,2H), 6.90 (d, 1H), 7.81(m, 1H), 7.91(m, 1H), 8.01(d, 1H), 8.48(m, 1H),8.79(d, 1H) LRMS: m/z ES⁺ 505[MNa⁺]

[0961] A Trifluoroacetic acid was used for the deprotection; the productwas isolated as the ditrifluoroacetate salt

Preparation 228-A1-(2-Pyrrolidin-1-yl-ethyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

[0962]

Preparation 228-B2-(2-Pyrrolidin-1-yl-ethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

[0963]

[0964] 1,4,6,7-Tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acidtert-butyl ester (1.8 g, 8.06 mmol)(EP1057814, Example 2c) was added to1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1.65 g, 9.67 mmol) andpotassium carbonate (3.34 g, 24.2 mmol) in N,N-dimethylformamide (35 ml)and the mixture was heated at 65° C. for 26 hours, then cooled to roomtemperature and stirred for 72 hours. The solvent was evaporated underreduced pressure and the residue was dissolved in 2N sodium hydroxidesolution. The aqueous mixture was extracted with ethyl acetate (×2) andthe combined organic layers were dried over magnesium sulphate andevaporated under reduced pressure. The residue was purified bychromatography on silica gel using ammonium hydroxide, methanol andethyl acetate in dichloromethane as eluant (gradient from 0:0:50:50 to0:0.1:50:50 to 0.5:5:0:95) to give the title compounds from preparation228-A and preparation 228-B as a mixture of isomers (300 mg).

[0965] LRMS: m/z ES⁺ 321 [MH⁺]

Preparation 229-A 1-(2-Pyrrolidin-1-yl-ethyl)-4,5,67-tetrahydro-1H-pyrazolo[4,3-c]pyridine ditrifluoroacetate

[0966]

Preparation 229-B2-(2-Pyrrolidin-1-yl-ethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridineditrifluoroacetate

[0967]

[0968] Trifluoroacetic acid (2 ml) was added to the product frompreparation 228 (equimolar mixture preparation 228-A and preparation228-B, 300 mg, 0.94 mmol) in dichloromethane under a nitrogenatmosphere. The mixture was stirred at room temperature for 1.5 hoursand then the solvent was evaporated under reduced pressure. Residualtrifluoroacetic acid was removed by dichloromethane azeotrope (×3) togive a mixture of the title compound from preparation 232-A containing40% by weight the title compound from preparation 232-B as a brown gum(792 mg).

[0969] LRMS: m/z ES⁺ 221 [MH⁺]

Preparation 2302-[2-Fluoro-4-methoxy-6-(tetrahydro-pyran-4-yl)-phenyl]-4,4-dimethyl-4,5-dihydro-oxazole

[0970]

[0971] Magnesium turnings (2.4 g, 100 mmol) were added to4-chlorotetrahydropyran (12 g, 100 mmol) in tetrahydrofuran (100 ml)followed by a crystal of iodine. After initiation of the reaction themixture reached reflux without external heating. When the reaction hadsubsided, the mixture was stirred at room temperature for 2 hours. Theabove tetrahydropyran-4-yl magnesium chloride solution (50 ml) was addeddropwise to the fluoro compound from preparation 2 (4.82 g, 20 mmol) intetrahydrofuran (20 ml) at 0° C. and the mixture was warmed to roomtemperature and was stirred for 2 hours. The reaction mixture wasdiluted with water and filtered through Arbocel®. The solution wasextracted with ethyl acetate and the organic layer was washed with brineand dried over magnesium sulphate and evaporated under reduced pressure.The residue was purified by chromatography on silica gel using ethylacetate in dichloromethane as eluant (gradient from 0:100 to 40:60) togive the title compound as a white solid (6.5 g).

[0972]¹H-nmr (CDCl₃, 400 MHz) δ: 1.40 (s, 6H), 1.95 (m, 4H), 3.14 (m,1H), 3.46 (m, 2H), 3.79 (s, 3H), 4.05 (m, 2H), 4.10 (s, 2H), 6.50 (d,1H), 6.62 (s, 1H)

[0973] LRMS: m/z (ES⁺) 330 [MNa⁺]

Preparation 2312-Fluoro-4-methoxy-6-(tetrahydro-pyran-4-yl)-benzonitrile

[0974]

[0975] Phosphorous oxychloride (6.14 g, 40 mmol) was added to theoxazolidine from preparation 230 (6.42 g, 21 mmol) in ethyl acetate (75ml) and pyridine (15.8 g, 0.2 mol) and the mixture was heated underreflux for 9 hours. The reaction mixture was cooled to room temperatureand was added to ice and water. The mixture was extracted with ethylacetate and the organic layer was washed with 2N hydrochloric acid (40ml), brine (30 ml) and dried over magnesium sulphate and evaporatedunder reduced pressure. The residue was purified by chromatography onsilica gel using ethyl acetate in dichloromethane as eluant (gradientfrom 0:100 to 10:90) to give the title compound as a white solid (4.3g).

[0976]¹H-nmr (CDCl₃, 400 MHz) δ: 1.80 (m, 4H), 3.17 (m, 1H), 3.59 (m,2H), 3.85 (s, 3H), 4.08 (m, 2H), 6.57 (d, 1H), 6.68 (s, 1H)

[0977] LRMS: m/z (ES⁺) 258 [MNa⁺]

Preparation 2322-(2-Fluoro-6-isopropyl-4-methoxy-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole

[0978]

[0979] Isopropyl magnesium chloride (2M in tetrahydrofuran, 0.5 ml, 1mmol) was added dropwise to the fluoro compound from preparation 2 (241mg, 1 mmol) in tetrahydrofuran (5 ml) at 0° C. The reaction mixture wasstirred at 0° C. for 15 minutes and then was stirred at room temperaturefor 16 hours. The reaction mixture was added to water and the solutionwas extracted with dichloromethane (3×30 ml). The combined organicsolutions were dried over magnesium sulphate and evaporated underreduced pressure. The residue was purified by chromatography on silicagel using ethyl acetate in hexane as eluant (gradient from 0:100 to30:70) to give the title compound as a colourless oil (110 mg).

[0980]¹H-nmr (CDCl₃, 400 MHz) δ: 1.21 (d, 6H), 1.39 (s, 6H), 3.28 (m,1H), 3.80 (s, 3H), 4.08 (s, 2H), 6.47 (d, 1H), 6.65 (s, 1H)

[0981] LRMS: m/z (ES⁺) 266 [MH⁺]

Preparation 233 2-Fluoro-6-isopropyl-4-methoxy-benzonitrile

[0982]

[0983] The title compound was obtained from the compound frompreparation 232 (2.43 g, 9.17 mmol) in 95% yield following the proceduredescribed in preparation 231.

[0984]¹H-nmr (CDCl₃, 400 MHz) δ: 1.30 (d, 6H), 3.31 (m, 1H), 6.83 (s,3H), 6.55 (d, 1H), 6.67 (s, 1H)

[0985] LRMS: m/z (ES⁺) 216 [MNa⁺]

Preparation 2342-Fluoro-4-methoxy-6-(tetrahydro-furan-3-yloxy)-benzonitrile

[0986]

[0987] Sodium hydride (60% in mineral oil, 0.83 g, 21 mmol) was addedportionwise to 3-hydroxytetrahydrofuran (1.82 g, 21 mmol) intetrahydrofuran (40 ml) at 0° C. under a nitrogen atmosphere. Thesuspension was warmed to room temperature and was stirred for 1 hour.The mixture formed was added over 30 minutes to2,6-difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172)(3.5 g, 21 mmol) in tetrahydrofuran (50 ml) and the resulting solutionwas held at room temperature for 16 hours. Water (75 ml) was added andthe aqueous mixture was extracted with ethyl acetate (3×200 ml) Thecombined organic solutions were dried over magnesium sulphate andevaporated under reduced pressure. The material obtained was dried undervacuum to give the title compound as a brown solid (5.1 g).

[0988]¹H-nmr (CDCl₃, 400 MHz) δ: 2.20 (m, 2H), 3.84 (s, 3H), 4.00 (m,4H), 4.95 (m, 1H), 6.18 (s, 1H), 6.32 (d, 1H)

[0989] LRMS: m/z ES⁺ 260 [MNa⁺]

Preparation 235 2-Fluoro-6-isopropoxy-4-methoxy-benzonitrile

[0990]

[0991] The title compound was obtained from2,6-difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172)in 49% yield following the procedure described in preparation 234.

[0992]¹H-nmr (CDCl₃, 400 MHz) δ: 1.40 (d, 6H), 3.85 (s, 3H), 4.59 (m,1H), 6.24 (m, 2H)

[0993] LRMS: m/z ES⁺ 210 [MH⁺]

Preparation 236 2-Cyclobutoxy-6-fluoro-4-methoxy-benzonitrile

[0994]

[0995] The title compound was obtained from2,6-difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172)in 80% yield following the procedure described in preparation 234.

[0996]¹H-nmr (CDCl₃, 400 MHz) δ: 1.68 (m, 1H), 1.88 (m, 1H), 2.23 (m,2H), 2.42 (m, 2H), 3.78 (s, 3H), 4.65 (m, 1H), 6.06 (s, 1H), 6.24 (d,1H)

[0997] LRMS: m/z (ES⁺) 244 [MNa⁺]

Preparation 237 2-Fluoro-4-methoxy-6-(2-methoxy-ethoxy)-benzonitrile

[0998]

[0999] Sodium hydride (60% in mineral oil, 0.88 g, 22 mmol) was added to2-methoxyethanol (1.84 g, 24 mmol) in tetrahydrofuran (20 ml) and themixture was stirred at room temperature for 20 minutes.2,6-Difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172)(3.38 g, 20 mmol) was added and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was poured into water andthe solution was extracted with dichloromethane (3×50 ml). The combinedorganic solutions were dried over magnesium sulphate and evaporatedunder reduced pressure. The residue was purified by chromatography onsilica gel using methanol in dichloromethane as eluant (gradient from0:100 to 3:97) to give the title compound (3.8 g).

[1000]¹H-nmr (CDCl₃, 400 MHz) δ: 3.46 (s, 3H), 3.78 (t, 2H), 3.81 (s,3H), 4.20 (t, 2H), 6.30 (m, 2H)

[1001] LRMS: m/z ES⁺ 248 [MNa⁺]

Preparation 238 2-Azido-4-methoxy-6-(2-methoxy-ethoxy)-benzonitrile

[1002]

[1003] The fluoro compound from preparation 237 (3.6 g, 16 mmol) wasadded to sodium azide (1.56 g, 24 mmol) in N,N-dimethylformamide (25 ml)and the mixture was heated at 100° C. for 8 hours. The reaction mixturewas cooled to room temperature and was added to water. The aqueousmixture was extracted with dichloromethane (3×60 ml) and the combinedorganic solutions were dried over magnesium sulphate and evaporatedunder reduced pressure. The residue was purified by chromatography onsilica gel using ethyl acetate in dichloromethane as eluant (gradientfrom 0:100 to 20:80) to give the title compound (3.51 g).

[1004]¹H-nmr (CDCl₃, 400 MHz) δ: 3.47 (s, 3H), 3.79 (t, 2H), 3.86 (s,3H), 4.20 (t, 2H), 6.30 (2×s, 2H)

[1005] LRMS: m/z ES⁺ 248 [MNa⁺]

Preparation 239 2-Amino-4-methoxy-6-(2-methoxy-ethoxy)-benzonitrile

[1006]

[1007] The azide from preparation 238 (3.50 g, 14.1 mmol) was suspendedin methanol (100 ml) and magnesium turnings (1.68 g, 70 mmol) wereadded. The mixture was stirred for 18 hours and then 1N citric acid wasadded. The aqueous mixture was extracted with dichloromethane (3×100 ml)and the combined organic solutions were dried over magnesium sulphateand evaporated under reduced pressure. The residue was purified bychromatography on silica gel using methanol in dichloromethane as eluant(gradient from 0:100 to 5:95). The material obtained was triturated withdiethyl ether to give the title compound as a white solid (1.78 g).

[1008]¹H-nmr (CDCl₃, 400 MHz) δ: 3.43 (s, 3H), 3.77 (m, 5H), 4.12 (t,2H), 4.37 (s, 2H), 5.82 (s, 1H), 5.86 (s, 1H)

[1009] LRMS: m/z ES⁺ 245 [MNa⁺]

Preparation 240 2-Chloro-6-fluoro-4-methoxy-benzonitrile

[1010]

[1011] A solution of sodium nitrite (3.73 g, 54 mmol) in water (20 ml)was added to the amino compound from preparation 291 (8.3 g, 50 mmol) inconcentrated hydrochloric acid at −10° C. at a rate that maintained thetemperature below −5° C. The solution was stirred at −5° C. for 1 hourand then was added dropwise to copper (I) chloride (9.9 g, 0.1 mol) inwater (100 ml) at −10° C. The reaction mixture was warmed to roomtemperature and was stirred for 16 hours and then the aqueous mixturewas extracted with dichloromethane (×3). The combined organic solutionswere washed with 1M sodium hydroxide solution (2×250 ml) and water (250ml) then dried over sodium sulphate and evaporated under reducedpressure. The residue was purified by chromatography on silica gel usingcyclohexane in dichloromethane as eluant (25:75) to give the titlecompound as a white solid (6.5 g).

[1012]¹H-nmr (CDCl₃, 400 MHz) δ: 3.87 (s, 3H), 6.65 (dd, 1H), 6.85 (d,1H)

[1013] LRMS: m/z (ES⁺) 208 [MNa⁺]

Preparation 241 2-Fluoro-6-iodo-4-methoxy-benzonitrile

[1014]

[1015] Sodium nitrite (227 mg, 3.3 mmol) in water (1 ml) was addeddropwise to the amino compound from preparation 291 (500 mg, 3 mmol) inconcentrated hydrochloric acid (10 ml) at −10° C. The mixture wasstirred at −10° C. for 1 hour and then was added dropwise to potassiumiodide (996 mg, 6 mmol) in water (5 ml) at −10° C. The reaction mixturewas warmed to room temperature and was stirred for 72 hours. Thereaction mixture was extracted with dichloromethane (3×50 ml) and thecombined organic extracts were washed with 10% sodium metabisulphitesolution (100 ml), 1M sodium hydroxide solution (100 ml) and water (100ml) The organic solution was dried over magnesium sulphate andevaporated under reduced pressure to give the title compound as a yellowsolid (751 mg).

[1016]¹H-nmr (DMSOd₆ 400 MHz) δ: 3.85 (s, 3H), 7.15 (d, 1H), 7.45 (s,1H)

[1017] LRMS: m/z ES⁺ 300 [MNa⁺]

Preparation 242 2-Amino-4-methoxy-6-(tetrahydro-pyran-4-yl)-benzonitrile

[1018]

[1019] Ammonia gas was bubbled into dimethylsulphoxide (30 ml) for 20minutes and the fluoro compound from preparation 231 (4.2 g, 17.9 mmol)was added and the mixture was heated at 150° C. for 18 hours. Thereaction mixture was cooled to room temperature and was added to ethylacetate (200 ml). The organic solution was washed with water (100 ml),1N citric acid (40 ml) and brine (40 ml), then dried over magnesiumsulphate and evaporated under reduced pressure. The residue was purifiedby chromatography on silica gel using ethyl acetate in dichloromethaneas eluant (gradient from 0:100 to 25:75) to give the title compound as awhite solid (1.64 g).

[1020]¹H-nmr (CDCl₃, 400 MHz) δ: 1.79 (m, 4H), 3.06 (m, 1H), 3.57 (m,1H), 3.79 (s, 3H), 4.06 (m, 2H), 4.39 (s, 2H), 6.08 (d, 1H), 6.23 (s,1H)

[1021] LRMS: m/z (ES⁺) 255 [MNa⁺]

Preparations 243 to 248

[1022] The compounds of the following tabulated preparations, of thegeneral formula:

[1023] were prepared by a similar method to that of preparation 242 fromthe appropriate fluoro compound. Prep R Spectroscopic Data 243

¹H-nmr(CDCl₃, 400 MHz) δ: 1.28(d, 6H), 3.19(m, 1H), 3.75(s, 3H), 4.35(s,2H), 6.06(s, 1H), 6.24(s, 1H) LRMS: m/z(ES⁺) 213[MNa⁺] 244

¹H-nmr(CDCl₃, 400 MHz) δ: 2.18(m, 2H), 3.75(s, 3H), 3.98(m, 4H), 4.38(s,2H), 4.90(m, 1H), 5.72(s, 1H), 5.81(s, 1H) LRMS: m/z ES⁺ 257[MNa⁺] 245

¹H-nmr(CDCl₃, 400 MHz) δ: 1.36(d, 6H), 3.77(s, 3H), 4.35(s, 2H), 4.53(m,1H), 5.81(m, 2H) LRMS: m/z ES⁺ 229[MNa⁺] 246 Cl ¹H-nmr(CDCl₃, 400 MHz)δ: 3.78(s, 3H), 4.50(s, 2H), 6.09(s, 1H), 6.39(s, 1H) LRMS: m/z(ES⁻)181, 183[M⁻H] 247

¹H-nmr(CDCl₃, 400 MHz) δ: 1.67(m, 1H), 1.87(m, 1H), 2.21(m, 2H), 2.40(m,2H), 3.74(s, 3H), 4.35(s, 2H), 4.61(m, 1H), 4.65(s, 1H), 5.79(s, 1H)LRMS: m/z(ES⁺) 241[MNa⁺] 248 I ¹H-nmr(CDCl₃, 400 MHz) δ: 3.77(s, 3H),4.43(s, 2H), 6.15(s, 1H), 6.80(s, 1H) LRMS: m/z ES⁺ 297[MNa⁺]

Preparation 2492-Amino-6-(4,5-dihydro-furan-2-yl)-4-methoxy-benzonitrile

[1024]

[1025] The iodo compound from preparation 248 (2.1 g, 7.7 mmol) in1,4-dioxane (15 ml) was added to a solution oftris-(dibenzylideneacetone)dipalladium(0) (174 mg, 0.19 mmol) andtri-furan-2-yl-phosphine (88.2 mg, 0.38 mmol) in 1,4-dioxane (15 ml)under an argon atmosphere. Tributyl-(4,5-dihydro-furan-2-yl)-stannane(5.5kg, 15.3 mmol) was added and the mixture was heated under reflux for1.25 hours and then was cooled to room temperature. 1M Potassiumfluoride solution (22 ml) was added and the mixture was stirred at roomtemperature for 30 minutes. The mixture was filtered and the filter cakewas washed with ethyl acetate (75 ml). The filtrate was diluted withwater and extracted with ethyl acetate (2×75 ml), the combined organicsolutions were dried over magnesium sulphate and evaporated underreduced pressure. The residue was purified by chromatography on silicagel using ethyl acetate in cyclohexane as eluant (10:90). The materialobtained was dissolved in acetonitrile and was washed with hexane (2×60ml). The acetonitrile layer was separated and evaporated under reducedpressure to give the title compound as a yellow solid (1.34 g).

[1026]¹H-nmr (DMSOd₆ 400 MHz) δ: 2.78 (m, 2H), 3.72 (s, 3H), 4.37 (t,2H), 5.76 (t, 1H), 5.84 (s, 2H), 6.33 (s, 1H), 6.39 (s, 1H)

[1027] LRMS: m/z ES⁺ 239 [MNa⁺]

Preparation 250 2-Amino-4-methoxy-6-(tetrahydro-furan-2-yl)-benzonitrile

[1028]

[1029] The dihydrofuran from preparation 249 (1.29 g, 5.96 mmol) wasdissolved in methanol (125 ml) and the solution was purged with argon.10% Palladium on active carbon (1.29 g) and ammonium formate (12.9 g,0.2 mol) were added and the mixture was heated under reflux for 15minutes. The mixture was cooled and filtered through Arbocel®. Thefilter cake was washed with ethanol. The combined organic solutions wereevaporated under reduced pressure and the residue was partitionedbetween ethyl acetate (200 ml) and water (200 ml). Sodium carbonate wasadded to give pH10 and the phases were separated. The aqueous phase wasextracted with ethyl acetate (2×50 ml) and the combined organicsolutions were dried over magnesium sulphate and evaporated underreduced pressure. The residue was purified by chromatography on silicagel using ethyl acetate in cyclohexane as eluant (10:90) and thematerial obtained was co-evaporated with diethyl ether to give the titlecompound as a white solid (473 mg).

[1030]¹H-nmr (CDCl₃, 400 MHz) δ: 1.75 (m, 1H), 2.00 (m, 2H), 2.51 (m,1H), 3.79 (s, 3H), 3.94 (q, 1H), 4.13 (q, 1H), 4.35 (s, 2H), 5.02 (t,1H), 6.10 (s, 1H), 6.48 (s, 1H)

[1031] LRMS: m/z ES⁺ 241 [MNa⁺]

Preparation 2517-Methoxy-5-(tetrahydro-pyran-4-yl)-1H-quinazoline-2,4-dione

[1032]

[1033] 1,8-Diazabicyclo[5.4.0]undec-7-ene (3 ml) was added to thenitrile from preparation 242 (1.6 g, 6.9 mmol) in N,N-dimethylformamide(15 ml) and the solution was cooled to −78° C. and solid carbon dioxide(6 g) was added. The mixture was heated at 140° C. and 600 psi for 18hours and then cooled to room temperature and added to water. Theaqueous solution was acidified with 2N hydrochloric acid and the solidformed was isolated by filtration. The filter cake was washed with waterand dried at 100° C. under vacuum to give the title compound as a whitesolid (1.81 g).

[1034]¹H-nmr (DMSOd₆ 400 MHz) δ: 1.61 (m, 4H), 3.40 (m, 2H), 3.79 (s,3H), 3.92 (m, 1H), 6.52 (d, 1H), 6.60 (s, 1H)

[1035] LRMS: m/z (ES⁺) 299 [MNa⁺]

Preparations 252 to 257

[1036] The compounds of the following tabulated preparations of thegeneral formula:

[1037] were prepared by a similar method to that of preparation 251 fromthe appropriate nitrile compound. Prep R Spectroscopic Data 252

¹H-nmr(DMSOd₆, 400 MHz) δ: 1.13(d, 6H), 3.79(s, 3H), 4.49(m, 1H),6.52(d, 1H), 6.61(d, 1H) LRMS: m/z(ES⁺) 491[2MNa⁺] 253

¹H-nmr(DMSOd₆, 400 MHz) δ: 1.99(m, 1H), 2.15(m, 1H), 3.80(m, 7H),5.01(m, 1H), 6.08(s, 1H), 6.23(s, 1H) LRMS: m/z ES⁺ 301[MNa⁺] 254

¹H-nmr(DMSOd₆, 400 MHz) δ: 3.35(s, 3H), 3.66(t, 2H), 3.78(s, 3H),4.10(m, 2H), 6.24(m, 2H) LRMS: m/z(ES⁺) 555[2MNa⁺] 255

¹H-nmr(DMSOd₆, 400 MHz) δ: 1.28(d, 6H), 3.78(s, 3H), 4.59(m, 1H),6.22(s, 2H) LRMS: m/z ES⁺ 273[MNa⁺] 256 Cl ¹H-nmr(DMSOd₆, 400 MHz) δ:3.80(s, 3H), 6.59(s, 1H), 6.79(s, 1H) LRMS: m/z(ES⁻) 225, 227[M⁻H] 257

¹H-nmr(DMSOd₆, 400 MHz) δ: 1.47(m, 1H), 1.73(m, 1H), 1.83(m, 1H),2.45(m, 1H), 3.80(m, 4H), 4.03(m, 1H), 5.75(t, 1H), 6.52(s, 1H), 6.80(s,1H), 10.98(2xs, 2H) LRMS: m/z ES⁺ 262[MNa⁺]

Preparation 258 4-Amino-5-cyclobutoxy-7-methoxy-1H-quinazolin-2-one

[1038]

[1039] Trifluoroacetic acid (6.7 ml, 84 mmol) was added to a suspensionof sodium cyanate (5.4 g, 84 mmol) in dichloromethane (120 ml) at 0° C.under a nitrogen atmosphere. The mixture was warmed to room temperatureand was stirred for 45 minutes. The amino nitrile from preparation 247(7.3 g, 33 mmol) was added in dichloromethane (100 ml) and the reactionmixture was stirred at room temperature for 4 hours. The solid formedwas isolated by filtration and the filter cake was washed with water andthen with diethyl ether. The residue was re-suspended in water and wasstirred for 2 hours and then isolated by filtration. The filter cake waswashed with water and diethyl ether then dried under vacuum to give thetitle compound as a white solid (5.9 g).

[1040]¹H-nmr (DMSOd₆ 400 MHz) δ: 1.59 (m, 1H), 1.78 (m, 1H), 2.00 (m,2H), 3.74 (s, 3H), 4.77 (m, 1H), 6.05 (s, 1H), 6.21 (s, 2H), 7.34 (s,1H), 8.20 (s, 1H)

[1041] LRMS: m/z ES⁺ 284 [MNa⁺]

Preparation 259 2-Chloro-5-cyclobutoxy-7-methoxy-quinazolin-4-ylamine

[1042]

[1043] The quinazolinone from preparation 258 (3 g, 11 mmol) wassuspended in acetonitrile (30 ml) and tetraethylammonium chloride (2.1g, 11 mmol), N′N-dimethylaniline (1.46 ml, 11 mmol) and phosphorousoxychloride (5.35 ml, 57 mmol) were added. The mixture was heated to 75°C. over 20 minutes and then was cooled to room temperature. The mixturewas added to ice and then saturated sodium carbonate solution was addedto give pH 9. The solution was extracted with dichloromethane containing5% methanol (×3). The combined organic solutions were dried over sodiumsulphate and evaporated under reduced pressure. The residue was purifiedby chromatography on silica gel using methanol in dichloromethane aseluant (gradient from 0:100 to 10:90) to give the title compound as awhite solid (1.11 g).

[1044]¹H-nmr (CDCl₃, 400 MHz) δ: 1.78 (m, 1H), 1.96 (m, 1H), 2.23 (m,2H), 2.56 (m, 2H), 3.83 (s, 3H), 4.74 (m, 1H), 5.90 (s, 1H), 6.20 (s,1H), 6.70 (s, 1H), 7.52 (s, 1H)

[1045] LRMS: m/z ES⁺ 280, 282 [MH⁺]

Preparation 260 2,4-Dichloro-5-cyclobutoxy-7-methoxy-quinazoline

[1046]

[1047] Antimony (III) chloride (4 g, 17.4 mmol) was added to asuspension of the amino compound from preparation 259 (2.43 g, 8.7 mmol)in dichloromethane (50 ml) and acetonitrile (50 ml) and the mixture wascooled to −10° C. and tert-butyl nitrite (3.6 ml, 30.4 mmol) was addeddropwise. The mixture was stirred at −10° C. for 1 hour, at roomtemperature for 1.5 hours and under reflux for 16 hours. The reactionmixture was cooled to room temperature and was added to ice. The mixturewas filtered and the phases were separated. The aqueous phase wasextracted with dichloromethane (×2) and the combined organic solutionswere dried over sodium sulphate and evaporated under reduced pressure.The residue was purified by chromatography on silica gel using ethylacetate in pentane as eluant (gradient from 5:95 to 15:85) to give thetitle compound as an off white solid (200 mg).

[1048]¹H-nmr (CDCl₃, 400 MHz) δ: 1.79 (m, 1H), 1.98 (m, 1H), 2.33 (m,3H), 2.55 (m, 2H), 3.93 (m, 1H), 6.40 (s, 1H), 6.88 (s, 1H)

[1049] LRMS: m/z ES⁺ 321, 323 [MNa⁺]

Preparation 2612,4-Dichloro-7-methoxy-5-(tetrahydro-pyran-4-yl)-quinazoline

[1050]

[1051] The quinazolinedione from preparation 251 (1.76 g) was suspendedin phosphorous oxychloride (20 ml) and N,N-diisopropylethylamine (1.98g, 15.3 mmol) was added dropwise. The mixture was heated at 90° C. for 2hours and then was heated under reflux for 3 hours. The reaction mixturewas cooled to room temperature and evaporated under reduced pressure.The residue was partitioned between water and ethyl acetate, the organicphase separated and washed with water and brine, then dried overmagnesium sulphate and evaporated under reduced pressure. The residuewas purified by chromatography on silica gel using ethyl acetate indichloromethane as eluant (gradient from 0:100 to 25:75) to give thetitle compound as a white solid (1.2 g).

[1052]¹H-nmr (CDCl₃, 400 MHz) δ: 1.88 (m, 4H), 3.62 (m, 2H), 3.97 (s,3H), 4.12 (m, 2H), 4.35 (m, 1H), 7.19 (dd, 1H), 7.22 (d, 1H)

[1053] LRMS: m/z (ES⁺) 335, 337 [MNa⁺]

Preparations 262 to 267

[1054] The compounds of the following tabulated preparations of thegeneral formula:

[1055] were prepared by a similar method to that of preparation 261using the appropriate quinazolinedione compound. Prep R SpectroscopicData 262

¹H-nmr(CDCl₃, 400 MHz) δ: 1.38(d, 6H), 3.95(s, 3H), 4.52(m, 1H), 7.15(s,1H), 7.29(d, 1H) LRMS: m/z(ES⁺) 271, 273[MNa⁺] 263

¹H-nmr(DMSOd₆, 400 MHz) δ: 2.10(m, 1H), 2.28(m, 1H), 3.90(m, 7H),5.29(m, 1H), 6.80(s, 1H), 6.99(s, 1H) LRMS: m/z ES⁺ 337, 339[MNa⁺] 264

¹H-nmr(CDCl₃, 400 MHz) δ: 3.48(s, 3H), 3.88(s, 2H), 3.94(s, 3H), 4.23(s,2H), 6.59(s, 1H), 6.90(s, 1H) LRMS: m/z ES⁺ 303, 305[MH⁺] 265

¹H-nmr(CDCl₃, 400 MHz) δ: 1.50(d, 6H), 3.93(s, 3H), 4.71(m, 1H), 6.55(s,1H), 6.87(s, 1H) LRMS: m/z ES⁺ 197[MH⁺] 266 Cl ¹H-nmr(CDCl₃, 400 MHz) δ:3.95(s, 3H), 7.22(s, 1H), 7.27(s, 1H) 267

¹H-nmr(CDCl₃, 400 MHz) δ: 1.91(m, 3H), 2.68(m, 1H), 3.99(m, 4H), 4.21(m,1H), 6.18(m, 1H), 7.19(d, 1H), 7.64(d, 1H) LRMS: m/z ES⁺ 321[MNa⁺]

Preparation 2682-Chloro-7-methoxy-5-(tetrahydro-pyran-4-yl)-3H-quinazolin-4-one

[1056]

[1057] The dichloride from preparation 261 (1.17 g, 3.74 mmol) was addedto 1,4-dioxane (20 ml) and 1M sodium hydroxide solution (20 ml) and themixture was stirred at room temperature for 2 hours. The reactionmixture was acidified with 2M hydrochloric acid (15 ml) and wasextracted with methanol in dichloromethane (10:90, 5×50 ml). Thecombined organic solutions were dried over magnesium sulphate andevaporated under reduced pressure. The residue was triturated withdiethyl ether to give the title compound as a white solid (0.98 g).

[1058]¹H-nmr (DMSOd₆ 400 MHz) δ: 1.64 (m, 4H), 3.42 (m, 2H), 3.85 (s,3H), 4.12 (m, 2H), 4.35 (m, 1H), 6.93 (s, 2H)

[1059] LRMS: m/z (ES⁻) 293, 295 [M−H]⁻

Preparations 269 to 275

[1060] The compounds of the following tabulated preparations of thegeneral formula:

[1061] were prepared by a similar method to that of preparation 268 fromthe appropriate dichloro compound. Prep R Spectroscopic Data 269

¹H-nmr(CDCl₃, 400 MHz) δ: 1.29(d, 6H), 3.92(s, 3H), 4.55(m, 1H), 6.93(d,1H), 7.01(s, 1H) LRMS: m/z(ES⁺) 275, 277[MNa⁺] 270

¹H-nmr(DMSOd₆, 400 MHz) δ: 2.00(m, 1H), 2.19(m, 1H), 3.80(m, 7H),5.08(m, 1H), 6.52(s, 1H), 6.62(s, 1H) LRMS: m/z ES⁺ 319, 321[MNa⁺] 271

¹H-nmr(DMSOd₆, 400 MHz) δ: 3.33(s, 3H), 3.68(t, 2H), 3.83(s, 3H),4.15(t, 2H), 6.56(d, 1H), 6.60(d, 1H) LRMS: m/z ES⁺ 307, 309[MH⁺] 272

¹H-nmr(DMSOd₆, 400 MHz) δ: 1.30(d, 6H), 3.83(s, 3H), 4.66(m, 1H),6.55(s, 1H), 6.60(s, 1H) LRMS: m/z ES⁺ 291[MNa⁺] 273 Cl ¹H-nmr(CDCl₃,400 MHz) δ: 3.88(s, 3H), 7.01(s, 1H), 7.13(s, 1H) LRMS: m/z(ES⁻) 243,245[M⁻H] 274

¹H-nmr(CDCl₃, 400 MHz) δ: 1.78(m, 1H), 1.92(m, 1H), 2.35(m, 2H), 2.52(m,2H), 3.88(s, 3H), 4.73(m, 1H), 6.30(s, 1H), 6.69(s, 1H), 10.83(s, 1H)LRMS: m/z ES⁻ 279, 281[M⁻H] 275

¹H-nmr(CDCl₃, 400 MHz) δ: 1.63(m, 1H), 1.94(m, 2H), 2.69(m, 1H), 3.90(s,3H), 4.18(m, 1H), 6.00(t, 1H), 6.96(d, 1H), 7.38(d, 1H), 10.03(s, 1H)LRMS: m/z ES⁺ 303[MNa⁺]

Preparation 276 2,6-Difluoro-4-methoxy-benzoic acid tert-butyl ester

[1062]

[1063] N,N-dimethylformamide di-tert-butyl acetal (75 ml, 0.31 mol) intoluene (60 ml) was added dropwise over 1.5 hours to2,6-difluoro-4-methoxy-benzoic acid (15 g, 80 mmol)(Mol. Cryst. Liq.Cryst. 1989, 172) in toluene (120 ml) at 80° C. under a nitrogenatmosphere. The mixture was stirred at 80° C. for 30 minutes and thencooled to room temperature. Ethyl acetate (100 ml) was added and theorganic solution was washed with saturated sodium hydrogen carbonatesolution (2×150 ml), brine (150 ml), dried over magnesium sulphate andevaporated under reduced pressure. The residue was purified bychromatography on silica gel using diethyl ether in pentane as eluant(10:90) to give the title compound as an oil (17.91 g).

[1064]¹H-nmr (CDCl₃, 400 MHz) δ: 1.58 (s, 9H), 3.79 (s, 3H), 6.43 (d,2H)

[1065] LRMS: m/z ES⁺ 267 [MNa⁺]

Preparation 277 2-Butylsulfanyl-6-fluoro-4-methoxy-benzoic acidtert-butyl ester

[1066]

[1067] The ester from preparation 276 (488 mg, 2 mmol) was added tobutane-1-thiol (321 μl, 3 mmol) and potassium carbonate (826 mg, 6 mmol)in 1-methyl-pyrrolidin-2-one (4 ml) and the mixture was heated at 120°C. for 23 hours. The reaction mixture was partitioned between water (20ml) and diethyl ether/pentane (50:50, 100 ml) and the phases wereseparated. The organic layer was washed with 1M sodium hydroxidesolution (2×10 ml) and water (10 ml), then dried over magnesium sulphateand evaporated under reduced pressure to give the title compound as anoil (562 mg).

[1068]¹H-nmr (CDCl₃, 400 MHz) δ: 0.93 (t, 3H), 1.42 (m, 2H), 1.59 (s,9H), 1.68 (m, 2H), 2.71 (t, 2H), 3.79 (s, 3H), 6.40 (d, 1H), 6.65 (s,1H)

Preparation 278 2-(Butane-1-sulfonyl)-6-fluoro-4-methoxy-benzoic acidtert-butyl ester

[1069]

[1070] The thioether from preparation 277 (550 mg, 1.5 mmol) wasdissolved in dichloromethane (15 ml) and 3-chloroperoxybenzoic (60-85%pure, 2.4 g) was added. The mixture was stirred for 2 hours and then wasdiluted with dichloromethane (50 ml). The mixture was washed with 30%potassium carbonate solution (2×50 ml) and brine (50 ml), then driedover magnesium sulphate and evaporated under reduced pressure. Theresidue was purified by chromatography on silica gel using diethyl etherin pentane as eluant (gradient from 10:90 to 20:80) to give the titlecompound as a gum (339 mg).

[1071]¹H-nmr (CDCl₃, 400 MHz) δ: 0.92 (t, 3H), 1.43 (m, 2H), 1.59 (s,9H), 1.71 (m, 2H), 3.37 (m, 2H), 3.87 (s, 3H), 6.82 (d, 1H), 7.30 (s,1H)

[1072] LRMS: m/z ES⁺ 369 [MNa⁺]

Preparation 279 2-(Butane-1-sulfonyl)-6-fluoro-4-methoxy-benzoic acid

[1073]

[1074] Trifluoroacetic acid (3 ml) was added to the ester frompreparation 278 (320 mg, 0.92 mmol) in dichloromethane (3 ml) and themixture was stirred for 2 hours at room temperature. The solvent wasevaporated under reduced pressure and the last traces of trifluoroaceticacid were removed by dichloromethane azeotrope (3×10 ml) to give thetitle compound as a gum (288 mg).

[1075]¹H-nmr (CDCl₃, 400 MHz) δ: 0.92 (t, 3H), 1.44 (m, 2H), 1.76 (m,2H), 3.40 (t, 2H), 3.92 (s, 3H), 6.88 (d, 1H), 7.37 (s, 1H)

[1076] LRMS: m/z (ES⁻) 289 [M−H]⁻

Preparation 280[2-(Butane-1-sulfonyl)-6-fluoro-4-methoxy-phenyl]-imidazol-1-yl-methanone

[1077]

[1078] The carboxylic acid from preparation 279 (288 mg, 0.92 mmol) wasdissolved in N,N-dimethylformamide (4 ml) and 1,1′-carbonyidiimidazole(164 mg, 1 mmol) was added under a nitrogen atmosphere. The reactionmixture was stirred at room temperature for 1.5 hours and then wasdiluted with N,N-dimethylformamide (2 ml). The resulting solution wasused without further elaboration in Example 127 and Example 128.

Preparation 281 2-Fluoro-4-methoxy-6-pyridin-2-yl-benzonitrile

[1079]

[1080] The iodo compound from preparation 241 (1 g, 3.6 mmol) was mixedwith 2-tributylstannanyl-pyridine (2.66 g, 7.2 mmol), copper (I) iodide(137 mg, 0.72 mmol), lithium chloride (612 mg, 14.2 mmol) andtetrakis(triphenylphosphine)palladium(0) (400 mg, 0.34 mmol) in1,4-dioxane (25 ml) and the mixture was heated under reflux for 4 hours.The reaction was cooled to room temperature and concentrated ammoniumhydroxide solution (5 ml) was added. The solution was partitionedbetween brine and dichloromethane and the aqueous phase was extractedwith dichloromethane. The combined organic solutions were dried overmagnesium sulphate and evaporated under reduced pressure. The residuewas purified by chromatography on silica gel using ethyl acetate inpentane as eluant (gradient from 50:50 to 100:0) to give the titlecompound as a pale yellow solid (0.95 g). LRMS: m/z ES⁺ 229 [MH⁺]

Preparation 282 2-Fluoro-4-methoxy-6-pyridin-2-yl-benzoic acid

[1081]

[1082] The nitrile from preparation 281 (500 mg) was added toconcentrated hydrochloric acid (15 ml) and the mixture was heated underreflux for 6 hours. The reaction mixture was cooled to room temperatureand adjusted to pH5 by addition of 5N sodium hydroxide. The solution wasextracted with dichloromethane (3×50 ml) and ethyl acetate (3×10 ml) andthe combined organic solutions were dried over magnesium sulphate andevaporated under reduced pressure to give the title compound (420 mg).

[1083] LRMS: m/z ES⁺ 248 [MH⁺]

Preparation 2832-(3-Fluoro-5-methoxy-2-methoxycarbonyl-phenyl)-1-methyl-pyridiniumiodide

[1084]

[1085] The pyridylbenzoic acid from preparation 282 (282 mg, 1.1 mmol)and iodomethane (1.42 g, 10 mmol) in acetonitrile (10 ml) were stirredat room temperature for 16 hours. N,N-Diisopropylethylamine (142 mg, 1.1mmol) was added and the mixture was stirred at room temperature for 4hours and then was heated under reflux for 2.5 hours. The reactionmixture was cooled to room temperature and was stirred for 16 hours. Thesolvent was evaporated under reduced pressure and the residue waspurified by chromatography on silica gel using methanol indichloromethane as eluant (10:90). The material obtained was trituratedwith diethyl ether to give the title compound as a yellow solid (416mg).

[1086]¹H-nmr (DMSOd₆ 400 MHz) δ: 3.60 (s, 3H), 3.90 (s, 3H), 4.00 (s,3H), 7.12 (s, 1H), 7.27 (d, 1H), 7.99 (d, 1H), 8.15 (m, 1H), 8.60 (m,1H), 9.12 (d, 1H)

[1087] LRMS: m/z ES⁺ 291 [MNa⁺]

Preparation 284 2-Fluoro-4-methoxy-6-(1-methyl-piperidin-2-yl)-benzoicacid methyl ester

[1088]

[1089] The pyridinium iodide from preparation 283 (410 mg, 1 mmol) wasadded to platinum oxide (100 mg) in methanol (50 ml) under a nitrogenatmosphere and ammonium formate (3.3 g) was added. The mixture washeated under reflux for 2 hours, cooled to room temperature and stirredfor 16 hours. Additional platinum oxide (100 mg) and ammonium formate(3.3 g) were added and the mixture was heated under reflux for 1 hour.The reaction mixture was cooled to room temperature, diluted withdichloromethane (150 ml) and filtered through Arbocel®. The filter cakewas washed with dichloromethane and water and the filtrate was dilutedwith water. The organic layer was separated, dried over magnesiumsulphate and evaporated under reduced pressure. The residue was purifiedby chromatography on silica gel using methanol in dichloromethane aseluant (gradient from 0:100 to 4:96) to give the title compound as anorange oil (150 mg).

[1090]¹H-nmr (CDCl₃, 400 MHz) δ: 1.63 (m, 6H), 2.00 (s, 3H), 2.10 (m,1H), 2.97 (m, 2H), 3.80 (s, 3H), 3.88 (s, 3H), 6.51 (d, 1H), 6.93 (s,1H)

[1091] LRMS: m/z ES⁺ 282 [MH⁺]

Preparation 285 2-Fluoro-4-methoxy-6-(1-methyl-piperidin-2-yl)-benzoicacid

[1092]

[1093] The methyl ester from preparation 284 (215 mg, 0.76 mmol) and 1Msodium hydroxide solution (0.8 ml, 0.8 mmol) were mixed in methanol (10ml) and the solution was heated under reflux for 2 hours. Additional 2Msodium hydroxide solution (1 ml, 2 mmol) was added and the mixture washeated under reflux for a further 6 hours. The reaction mixture wascooled to room temperature and 2M hydrochloric acid (1.5 ml) was added.The mixture was evaporated under reduced pressure and the residue waspurified by chromatography on silica gel using methanol and ammoniumhydroxide in dichloromethane as eluant (10:1:90). The material obtainedwas triturated with diethyl ether to give the title compound as a whitesolid (173 mg).

[1094]¹H-nmr (DMSOd₆ 400 MHz) δ: 1.98 (m, 9H), 2.47 (m, 1H), 3.27 (m,2H), 3.81 (s, 3H), 6.50 (s, 1H), 6.64 (d, 1H)

[1095] LRMS: m/z ES⁺ 268 [MH⁺]

Preparation 286N-[(7,8-Dihydro-5H-[1.6]naphthyridin-6-yl)-imino-methyl]-2-fluoro-4-methoxy-6-(1-methyl-piperidin-2-yl)-benzamide

[1096]

[1097] The guanidine from preparation 225 (121 mg, 0.3 mmol) wassuspended in N,N-dimethylformamide (3 ml) and sodium hydride (60% inmineral oil, 60 mg, 1.5 mmol) was added and the mixture was stirred atroom temperature for 20 minutes. The carboxylic acid from preparation285 (80 mg, 0.3 mmol) was suspended in dichloromethane (4 ml) containing1 drop of N,N-dimethylformamide. Oxalyl chloride (76 mg, 0.6 mmol) wasadded and the mixture was stirred for 10 minutes. The mixture wasevaporated under reduced pressure and the residue was redissolved indichloromethane (3 ml). The solution obtained was added to theguanidinium salt described above and the mixture was stirred at roomtemperature for 1 hour and then was acidified with 0.2N hydrochloricacid (50 ml). The solution was washed with dichloromethane (2×20 ml) andthen basified with 1M sodium hydroxide. The aqueous mixture wasextracted with dichloromethane (3×70 ml) and the combined extracts weredried over magnesium sulphate and evaporated under reduced pressure. Theresidue was purified by chromatography on silica gel using methanol andammonium hydroxide in dichloromethane as eluant (7:1:93) to give thetitle compound as a glass (78 mg).

[1098]¹H-nmr (CDCl₃, 400 MHz) δ: 1.23 (m, 1H), 1.65 (m, 5H), 1.84 (m,1H), 2.06 (s, 3H), 2.98 (m, 1H), 3.10 (t, 2H), 3.17 (m, 1H), 3.80 (s,3H), 3.86 (t, 2H), 4.75 (s, 2H), 6.50 (d, 1H), 6.94 (s, 1H), 7.11 (m,1H), 7.38 (d, 1H), 7.80 (s, 2H), 8.45 (d, 1H)

[1099] LRMS: m/z ES⁺ 426 [MH⁺]

Preparations 287 to 288

[1100] The compounds of the following tabulated preparations of thegeneral formula:

[1101] were prepared by a similar method to that of preparation 286using the carboxylic acid from preparation 285 and the appropriateguanidine. Prep R Spectroscopic Data 287

¹H-nmr(CDCl₃, 400 MHz) δ: 1.55(m, 5H), 2.08(m, 5H), 2.83(t, 2H), 3.00(m,1H), 3.20(m, 1H), 3.85(t, 2H), 4.82(m, 9H), 4.61(s, 2H), 6.51(d, 1H),6.61(s, 1H), 6.68(s, 1H), 6.97(s, 1H), 7.66(s, 2H) LRMS: m/z ES⁻483[M⁻H] 288

¹H-nmr(CDCl₃, 400 MHz) δ: 1.26(m, 1H), 1.62(m, 4H), 2.00(m, 5H), 2.87(t,2H), 2.95(m, 1H), 3.18(m, 1H), 3.38(s, 3H), 3.47(m, 2H), 3.55(t, 2H),3.80(m, 5H), 4.53(s, 2H), 4.72(m, 1H), 6.28(d, 1H), 6.49(d, 1H), 6.93(s,1H), 7.10(d, 1H), 7.70(s, 2H) LRMS: m/z ES⁻ 497[M⁻H]

Preparation 289 2-Amino-6-fluoro-4-methoxy-benzonitrile

[1102]

[1103] 2,6-Difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst.1989, 172) (200 mg, 1.18 mmol) was dissolved in ethanolic ammonia (2Msolution, 10 ml) and the mixture was heated at 140° C. in an autoclavefor 16 hours. The reaction mixture was cooled to room temperature andthe solvent was evaporated under reduced pressure. The residue waspurified by chromatography on silica gel using ethyl acetate in pentaneas eluant (20:80) to give the title compound as a white solid (165 mg).LRMS: m/z (ES⁺) 189 [MNa⁺]

Preparation 290 5-Chloromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

[1104]

[1105] Triethylamine (160 μl, 1,16 mmol) and then methane sulphonylchloride (72 μl, 0.92 mmol) were added to5-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butylester (202 mg, 0.77 mmol) (WO 02053558 p 59) in tetrahydrofuran (20 ml)and the mixture was stirred for 30 minutes. Tetrabutyl ammonium chloride(322 mg, 1.16 mmol) was added and the mixture was stirred for 2 hours atroom temperature. The reaction mixture was diluted with ethyl acetateand the organic solution was washed with sodium hydrogen carbonatesolution, dried over magnesium sulphate and evaporated under reducedpressure. The residue was purified by chromatography on silica gel usingmethanol in dichloromethane as eluant (2:98) to give the title compound(100 mg).

[1106]¹H-nmr (CDCl₃, 400 MHz) δ: 1.43 (s, 9H), 2.92 (m, 2H), 3.70 (m,2H), 4.39 (s, 4H), 7.18 (m, 3H)

[1107] LRMS: m/z (ES⁺) 304 [MNa⁺]

Preparation 2915-(2-Methyl-imidazol-1-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

[1108]

[1109] Sodium hydride (60% in mineral oil, 48 mg, 1.2 mmol) was added to2-methylimidazole (103 mg, 1.25 mmol) in tetrahydrofuran (10 ml) under anitrogen atmosphere. The mixture was stirred for 1.5 hours and then thechloromethyl compound from preparation 290 (325 mg, 1.15 mmol) was addedin tetrahydrofuran (1 ml). The mixture was heated under reflux for 2hours and then cooled to room temperature and stirred at roomtemperature for 16 hours. The reaction mixture was partitioned betweenethyl acetate (75 ml) and water (75 ml). The phases were separated andthe aqueous solution was extracted with ethyl acetate (2×35 ml). Thecombined ethyl acetate layers were dried over magnesium sulphate andevaporated under reduced pressure. The residue was purified bychromatography on silica gel using ammonium hydroxide and methanol indichloromethane as eluant (gradient from 0:0:100 to 0.5:5:95) to givethe title compound as a pale yellow oil (383 mg).

[1110]¹H-nmr (CDCl₃, 400 MHz) δ: 1.46, (s, 9H), 2.33 (s, 3H), 2.68 (t,2H), 3.66 (t, 2H), 4.59 (s, 2H), 4.97 (s, 2H), 6.65 (m, 2H), 6.96 (s,1H), 7.12 (m, 2H)

[1111] LRMS: m/z (ES⁺) 328 [MH⁺]

Preparation 2925-(2-Methyl-imidazol-1-ylmethyl)-1,2,3,4-tetrahydro-isoquinoline

[1112]

[1113] The protected amine from preparation 291 (290 mg, 0.88 mmol) wasdissolved in dichloromethane (12 ml) and was cooled to 4° C. under anitrogen atmosphere. Hydrogen chloride was bubbled into the solution for10 minutes to give a saturated solution. The reaction mixture wasstirred at 4° C. for 2.5 hours and then evaporated under reducedpressure. The residue was purified by chromatography on silica gel usingammonium hydroxide and methanol in dichloromethane as eluant (0.7:7:93).The material obtained was co evaporated with methanol to give the titlecompound as a pale yellow oil (180 mg).

[1114]¹H-nmr (CDCl₃, 400 MHz) δ: 2.33 (s, 3H), 2.60 (t, 2H), 3.18 (t,2H), 4.02 (s, 2H), 4.96 (s, 2H), 6.58 (d, 1H), 6.71 (s, 1H), 6.96 (s,1H), 6.99 (d, 1H), 7.10 (m, 1H)

[1115] LRMS: m/z (ES⁺) 228 [MH⁺]

Preparation 293[6-(5-Isopropyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-5,6,7,8-tetrahydro-[1,6]naphthyridin-2-ylmethyl]-carbamicacid tert-butyl ester

[1116]

[1117] The chloro compound from preparation 269 (101 mg, 0.4 mmol) wasadded to the amine from preparation 182 (116 mg, 0.44 mmol) andtriethylamine (168 μl, 1.2 mmol) in n-butanol (8 ml) and the mixture washeated under reflux for 2 hours. The reaction mixture was cooled to roomtemperature and was stirred for 16 hours. The solid formed was isolatedby filtration and was washed with diethyl ether (20 ml), water (10 ml)and diethyl ether (40 ml). The residue was dried under vacuum at 90° C.for 4 hours to give the title compound (160 mg).

[1118]¹H-nmr (DMSOd₆ 400 MHz) 5: 1.15 (d, 6H), 1.38 (s, 9H), 2.92 (t,2H), 3.80 (s, 3H), 3.92 (t, 2H), 4.15 (d, 2H), 4.53 (m, 1H), 4.78 (s,2H), 6.80 (d, 1H), 7.10 (m, 2H), 7.18 (m, 1H), 7.58 (d, 1H)

[1119] LRMS: m/z (ES⁺) 502 [MNa⁺]

Preparation 294(6-Benzyl-5,6,7,8-tetrahydro-[2,6]naphthyridin-1-ylmethyl)-methyl-amine

[1120]

[1121] Methylamine (40% in water, 1 ml) and acetic acid (60 μl, 1 mmol)were added to the aldehyde from preparation 35 (115 mg, 0.46 mmol) intetrahydrofuran (6 ml). The mixture was stirred at room temperature for5 minutes and then sodium triacetoxyborohydride (636 mg, 3 mmol) wasadded. The mixture was stirred at room temperature for 1 hour and thenwas acidified with 2M hydrochloric acid. The mixture was stirred for 10minutes and then basified with 1M sodium hydroxide. The reaction mixturewas extracted with 5% methanol in dichloromethane (4×40 ml) and thecombined organic solutions were dried over magnesium sulphate andevaporated under reduced pressure. The residue was purified bychromatography on silica gel using ammonium hydroxide and methanol indichloromethane as eluant (1:7:93) to give the title compound as ayellow oil (57 mg).

[1122] LRMS: m/z (ES⁺) 268 [MH⁺]

Preparation 295 (6-Benzyl-56,7,8-tetrahydro-[2,6]naphthyridin-1-ylmethyl)-methyl-carbamic acidtert-butyl ester

[1123]

[1124] The amine from preparation 294 (57 mg, 0.21 mmol) was dissolvedin dichloromethane and di-tert-butyl dicarbonate (55 mg, 0.25 mmol) wasadded. The mixture was stirred at room temperature for 2 hours then thereaction mixture was purified by chromatography on silica gel usingmethanol in dichloromethane as eluant (gradient 15 from 0:100 to 5:95)to give the title compound as an oil (61 mg).

[1125] LRMS: m/z (ES⁺) 390 [MNa⁺]

Preparation 296Methyl-(5,6,7,8-tetrahydro-[2,6]naphthyridin-1-ylmethyl)-carbamic acidtert-butyl ester

[1126]

[1127] The title compound was obtained as a colourless oil from thebenzyl compound from preparation 295 in 72% yield following theprocedure described in preparation 109.

[1128] LRMS: m/z (ES⁺) 300 [MNa⁺]

Preparation 297[2-(5-Isopropyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-12,3,4-tetrahydro-isoquinolin-5-ylmethyl]-methyl-carbamic acid tert-butylester

[1129]

[1130] The chloro compound from preparation 269 (31 mg, 0.12 mmol) wasadded to the amine from preparation 296 (34 mg, 0.12 mmol) in n-butanol(2 ml) containing N,N-diisopropylethylamine (129 μl, 1 mmol) and themixture was heated under reflux for 2.5 hours. The reaction mixture wascooled to room temperature and the solvent was evaporated under reducedpressure. The residue was purified by chromatography on silica gel usingmethanol in dichloromethane as eluant (gradient from 0:100 to 5:95) togive the title compound as an oil (59 mg).

[1131] LRMS: m/z (ES⁺) 516 [MNa⁺]

Preparation 298(6-Benzyl-5,6,7,8-tetrahydro-[1,6]naphthyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine

[1132]

[1133] Copper (II) sulphate (70 mg) was added to a solution of6-benzyl-2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine (0.75 g, 2.9mmol)(WO9830560 Example 33 b) in 2-pyrrolidin-1-yl-ethylamine (3 ml) andthe mixture was heated in an autoclave to 150° C. for 24 hours. Thereaction mixture was cooled to room temperature and was diluted withdichloromethane (50 ml). The solution was washed with 50% ammoniumhydroxide solution (50 ml). The phases were separated and the aqueousphase was extracted with dichloromethane (2×50 ml). The combined organicsolutions were dried over magnesium sulphate and evaporated underreduced pressure. The residue was purified by chromatography on silicagel using ammonium hydroxide and methanol in dichloromethane as eluant(gradient from 0.5:5:95 to 0.7:7:93) to give the title compound as ayellow oil (0.9 g). LRMS: m/z (ES⁺) 337 [MH⁺]

Preparation 299(2-Pyrrolidin-1-yl-ethyl)-(5,6,7,8-tetrahydro-[1,6]naphthyridin-2-yl)-amine

[1134]

[1135] The title compound was obtained from the benzyl compound frompreparation 298 (850 mg, 2.53 mmol) in 56% yield following the proceduredescribed in preparation 109.

[1136] LRMS: m/z (ES⁺) 247 [MH⁺]

Preparation 3005-Dimethylaminomethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester

[1137]

[1138] A solution of the aldehyde from preparation 25 (650 mg, 2.5mmol), and dimethylamine (2M in tetrahydrofuran, 1.75 ml, 3.5 mmol)intetrahydrofuran (5 ml) was stirred at room temperature for 3 hours.Sodium triacetoxyborohydride (1.47 g, 7 mmol) was added and the reactionstirred at room temperature for 18 hours. The mixture was partitionedbetween dichloromethane (50 ml) and sodium bicarbonate solution (30 ml),the layers separated, and the organic phase dried over magnesiumsulphate and evaporated under reduced pressure. The residual oil waspurified by chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (98:2:0.2) as eluant to afford thetitle compound, 602 mg.

[1139]¹H-nmr (CDCl₃, 400 MHz) δ: 1.50 (s, 9H), 2.20 (s, 6H), 2.90 (t,2H), 3.35 (s, 2H), 3.62 (t, 2H), 4.55 (s, 2H), 7.00 (m, 1H), 7.10 (d,2H).

Preparation 301Dimethyl-(1,2,3,4-tetrahydro-isoquinolin-5-ylmethyl)-amine hydrochloride

[1140]

[1141] The title compound was obtained from the protected amine frompreparation 300 (575 mg, 2 mmol) in quantitative yield following theprocedure described in preparation 212.

[1142] LRMS: m/z (ES⁺) 213 [MNa⁺]

Preparation 302(7-Benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-ethyl-methylamine

[1143]

[1144] A mixture of the chloride from preparation 39 (1.20 g, 4.68 mmol)and N-methylethylamine (2 ml) in dichloromethane (10 ml) was stirred atroom temperature for 18 hours, then under reflux for a further 8 hours.Acetonitrile (20 ml) was added, and the reaction stirred under refluxfor an additional 24 hours. The cooled mixture was concentrated underreduced pressure and the residue partitioned between dichloromethane and1% sodium bicarbonate solution. The organic layer was separated, driedover magnesium sulphate, and evaporated under reduced pressure. Thecrude product was purified by chromatography on silica gel usingdichloromethane:methanol (100:0 to 94:6) to afford the title compound asa pale yellow oil, 1.26 g.

[1145] LRMS: m/z (ES⁺) 283 [MH⁺]

Preparation 303Ethyl-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)amine

[1146]

[1147] A mixture of the protected amine from preparation 302 (1.17 g,4.15 mmol), ammonium formate (11.7 g) and 10% palladium on charcoal(1.11 g) in methanol (50 ml) was heated under reflux for 40 minutes. Thecooled mixture was filtered through Arbocel®, and the filtrate pouredinto 1N sodium hydroxide solution. This mixture was continuallyextracted with dichloromethane for 4 hours, and the organic extractevaporated under reduced pressure. The crude product was purified bychromatography on silica gel using dichloromethane:methanol:0.88 ammonia(90:9:1) to give the title product as a clear oil, 600 mg.

[1148] LRMS: m/z (ES⁺) 193 [MH⁺]

Preparation 304tert-Butyl[(tert-butoxycarbonyl)amino[](2-methoxyethyl)amino]methylenecarbamate

[1149]

[1150] Mercury chloride (11.94 g, 44 mmol) was added to a rapidlystirring solution of 2-methoxyethylamine (3.0 g, 40 mmol),1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (11.6 g, 40 mmol)and triethylamine (20.24 g, 200 mmol) in dichloromethane (100 ml), andthe reaction stirred at room temperature for 17 hours. The mixture wasfiltered, the filtrate evaporated under reduced pressure and the residuetriturated with hot ethyl acetate to remove further mercury salts. Thefiltrate was evaporated under reduced pressure and the crude productpurified by chromatography on silica gel using cyclohexane:ethyl acetate(95:5 to 85:15) to give the title compound as a colourless oil, 8.2 g.

[1151]¹H-nmr (CDCl₃, 400 MHz) δ: 1.45 (s, 18H), 3.38 (s, 3H), 3.48 (m,2H), 3.61 (m, 2H), 8.48 (bs, 1H).

[1152] LRMS: m/z (ES⁺) 340 [MNa⁺]

Preparation 305 N-(2-Methoxyethyl)quanidine trifluoroacetate

[1153]

[1154] A solution of the compound from preparation 304 (8.1 g, 25.5mmol) in trifluoroacetic acid (60 ml) was stirred at room temperaturefor 4 hours. The reaction was concentrated under reduced pressure andthe residue azeotroped with toluene and then dichloromethane. Theresidue was dried in vacuo at 60° C. to afford the title compound as acolourless oil, 8.77 g.

[1155]¹H-nmr (DMSOd₆, 400 MHz) δ: 3.23 (m, 5H), 3.40 (m, 2H), 7.05 (bs,4H), 7.55 (bs, 1H).

Preparation 3066-Benzyl-N*2*-(2-methoxyethyl)-5,6,78-tetrahydro-pyrido[4,3-d]pyrimidine-2,4-diamine

[1156]

[1157] Sodium hydride (156 mg, 60% dispersion in mineral oil, 3.9 mmol)was added portionwise to dry ethanol (3.5 ml), and once addition wascomplete, the guanidine from preparation 305 (621 mg, 1.8 mmol) wasadded, and the solution heated under reflux for 30 minutes.4-Amino-1-benzyl-1,2,5,6-tetrahydro-3-pyridinecarbonitrile (J. Med.Chem. 1991; 34 (9); 2899) (213 mg, 1 mmol) was added and the reactionheated under reflux for a further 17 hours. TLC analysis showed startingmaterial remaining, so the cooled reaction was diluted with ethanol (3ml), additional sodium hydride (10 mg, 60% dispersion in mineral oil,0.4 mmol) added, and the reaction heated under reflux for a further 24hours. The cooled mixture was partitioned between water (50 ml) andethyl acetate (50 ml), the layers separated, the aqueous extracted withethyl acetate (2×35 ml), and the combined organic solutions dried overmagnesium sulphate and evaporated under reduced pressure. The residualoil was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (97:3:0.2 to 90:10:1) and theproduct azeotroped with ether to afford the title compound as a yellowsolid, 58 mg.

[1158]¹H-nmr (CDCl₃, 400 MHz) δ: 2.68 (t, 2H), 2.78 (t, 2H), 3.22 (s,2H), 3.37 (s, 3H), 3.52 (m, 4H), 3.70 (s, 2H), 4.32 (bs, 2H), 4.95 (s,1H), 7.22-7.38 (m, 5H).

Preparation 307N*2*-(2-methoxyethyl)-5,6,78-tetrahydro-pyrido[4,3-d]pyrimidine-2,4-diamine

[1159]

[1160] Ammonium formate (10 g, 158.5 mmol) was added to a mixture of thecompound from preparation 306 (1.07 g, 3.41 mmol) and 10% palladium oncharcoal (1.0 g) in methanol (75 ml), and the reaction heated underreflux for 35 minutes. The cooled mixture was filtered through Arbocel®,washing well with ethanol, and the combined filtrates evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5 to85:12:2) and the product azeotroped with methanol and ether to affordthe title compound as a white solid, 218 mg.

[1161]¹H-nmr (DMSOd₆, 400 MHz) δ: 2.37 (m, 2H), 2.82-3.50 (m, 12H), 5.63(s, 1H0, 5.80 (bs, 2H).

[1162] LRMS: m/z (ES⁺) 224 [MH⁺]

[1163] The invention is illustrated by the following examples:

EXAMPLE 15-Cyclopropyl-2-(5-[(cyclopropylamino)methyl]-3,4-dihydro-2(1H)-isoquinolinyl)-7-methoxy-4(3H)-quinazolinone

[1164]

[1165] A mixture of the amine hydrochloride from preparation 95 (113 mg,0.41 mmol), the chloride from preparation 18 (86 mg, 0.34 mmol) anddiisopropylethylamine (0.36 mL, 1.7 mmol) in n-butanol (3 mL) wasstirred under reflux for 2.5 hours. The cooled reaction mixture wasconcentrated under reduced pressure and the residue partitioned betweendichloromethane (40 mL) and water. The layers were separated, theorganic phase washed with brine, dried (MgSO₄) and concentrated underreduced pressure. The crude product was purified by columnchromatography on silica gel using dichloromethane:methanol (97:3) aseluant to afford the title compound as a solid.

[1166]¹Hnmr (DMSOd6 400 MHz) δ: 0.13 (m, 2H), 0.35 (m, 2H), 0.63 (m,2H), 0.90 (m, 2H), 2.07 (m, 2H), 2.90 (m, 2H), 3.49 (m,1H), 3.68 (s,2H), 3.75 (m, 4H), 3.83 (m, 2H), 4.75 (s, 2H), 6.13 (m, 1H), 6.48 (m,1H), 7.05 (m, 1H), 7.15 (m, 1H), 10.82 (bs, 1H).

[1167] LRMS: m/z (ES⁺) 417 [MH⁺]

[1168] Microanalysis found: C, 69.56; H, 6.54; N, 13.04.C₂₅H₂₈N₄O₂;0.8H₂O requires C, 69.69; H, 6.92; N, 13.00%.

EXAMPLES 2 to 25

[1169]

[1170] General Method

[1171] To a solution of the chloro-quinazolinone from preparation 18 (1eq) in n-butanol (15 mL 5 per mmol) under nitrogen was addeddiisopropylethylamine (A) or triethylamine (B) (1.7-8.0 eq) and theappropriate secondary amine (1-2 eq). The resultant mixture was thenheated at reflux for 1-6 hours, cooled and the product was isolated byfiltration, washing with n-butanol and diethyl ether. Ex. no. R BaseYield %/Form Spectroscopic and Analytical Data  2 (a)

A 29 white solid ¹Hnmr(DMSOd₆, 400 MHz) δ: 0.30(m, 2H), 0.40(m, 2H),0.63(m, 2H), 0.94(m, 2H), 1.73(m, 1H), 2.10(s, 3H), 2.90(m, 2H), 3.46(m,1H), 3.60(s, 2H), 3.77(s, 3H), 3.80(m, 2H), 4.77(s, 2H), 6.13(s, 1H),6.53(s, 1H), 7.10(m, 3H), 10.84(bs, 1H). # LRMS: m/z(ES⁺)453[MNa⁺]Microanalysis found: C, 72.07; H, 7.00; N, 12.94. C₂₆H₃₀N₄O₂;0.2H₂O requires C, 71.93; H, 7.06; N, 12.90%.  3

B 76 white powder ¹Hnmr(DMSOd₆, 400 MHz) δ: 0.27(m, 1H), 0.57(m, 1H),0.63(m, 2H), 0.94(m, 2H), 1.35(m, 2H), 2.31(m, 2H), 2.77(d, 2H), 2.86(m,2H), 3.50(m, 3H), 3.74(s, 3H), 3.80(m, 2H), 4.76(s, 2H), 6.13(s, 1H),6.32(s, 1H), 7.10(m, 3H), 10.97(bs, 1H). # LRMS: m/z(ES⁺)465[MNa⁺]Microanalysis found: C, 72.83; H, 6.83; N, 12.52. C₂₇H₃₀N₄O₂;0.1C₄H₉OH requires C, 73.14; H, 6.94; N, 12.45%.  4

A 88 white solid ¹Hnmr(CDCl₃, 400 MHz) δ: 0.70(m, 2H), 0.97(m, 2H),2.26(s, 3H), 2.44(m, 8H), 3.06(t, 2H), 3.41(m, 1H), 3.46(s, 2H), 3.85(s,3H), 3.91(t, 2H), 4.87(s, 2H), 6.29(s, 1H), 6.67(d, 1H), 7.11(dd, 1H),7.15(d, 2H), 10.01(bs, 1H). LRMS: m/z(ES⁺) 482[MNa⁺]  5 (a)

A 43 white solid ¹Hnmr(DMSOd₆, 400 MHz) δ: 0.64(m, 2H), 0.90(m, 2H),1.67(m, 2H), 1.87(m, 2H), 2.17(s, 3H), 2.25(m, 2H), 2.47(s, 3H), 2.65(m,2H), 2.74(t, 2H), 3.49(m, 1H), 3.83(t, 2H), 4.37(m, 1H), 4.73(s, 2H),6.13(s, 1H), 6.52(s, 1H), 6.75(d, 1H), 6.83(d, 1H), 7.11(dd, 1H), #11.00(bs, 1H). LRMS: m/z(ES⁺) 461[MH⁺]. Microanalysis found: C, 69.55;H, 7.09; N, 11.78. C₂₇H₃₂N₄O₃; 0.3H₂O requires C, 69.59; H, 7.05; N,12.02%.  6

B 86 white powder ¹Hnmr(DMSOd₆, 400 MHz) δ: 0.62(m, 2H), 0.91(m, 2H),2.75(m, 5H), 3.50(m, 1H), 3.77(s, 3H), 3.86(t, 2H), 4.58(s, 2H), 6.13(s,1H), 6.25(m, 1H), 6.31(d, 1H), 6.53(s, 1H), 7.19(d, 1H), 10.99(bs, 1H).LRMS: m/z(ES⁺) 400[MNa⁺]. # Microanalysis found: C, 65.18; H, 6.03; N,18.03. C₂₁H₂₃N₅O₂; 0.5H₂O requires C, 65.27; H, 6.26; N, 18.12%.  7 (a)

A 35 white solid ¹H-nmr(DMSO-d₆, 400 MHz) δ: 0.64(m, 2H), 0.93(m, 2H),2.16(s, 6H), 2.93(t, 2H), 3.47(m, 3H), 3.76(s, 3H), 3.93(t, 2H), 4.78(s,2H), 6.15(s, 1H), 6.53(s, 1H), 7.24(d, 1H), 7.57(d, 1H), 11.08(bs, 1H).LRMS: m/z(ES⁻) 404[M − H⁻]. # Microanalysis found: C, 67.08; H, 6.72; N,16.98. C₂₃H₂₇N₅O₂; 0.3H₂O requires C, 67.23; H, 6.77; N, 17.04%.  8

A 51 white solid ¹H-nmr(DMSO-d₆, 400 MHz) δ: 0.64(m, 2H), 0.93(m, 2H),1.70(m, 4H), 2.53(m, 4H), 2.94(t, 2H), 3.50(m, 1H), 3.69(s, 2H), 3.76(s,3H), 3.93(t, 2H), 4.78(s, 2H), 6.15(s, 1H), 6.52(s, 1H), 7.25(d, 1H),7.56(d, 1H), 11.08(bs, 1H). LRMS: m/z(ES⁺) 454[MNa⁺]. # Microanalysisfound: C, 66.72; H, 6.63; N, 15.41. C₂₅H₂₉N₅O₂; 0.9H₂O requires C,67.06; H, 6.93; N, 15.64%.  9 (a)

B 31 ¹H-nmr(DMSO-d₆, 400 MHz) δ: 0.32(m, 1H), 0.63(m, 3H), 0.93(m, 2H),1.35(m, 2H), 2.37(m, 2H), 2.90(m, 4H), 3.49(m, 1H), 3.63(s, 2H), 3.78(s,3H), 3.92(t, 2H), 4.78(s, 2H), 6.15(s, 1H), 6.53(s, 1H), 7.18(d, 1H),7.57(d, 1H), 11.05(bs, 1H). # LRMS: m/z(ES⁺) 466[MNa⁺]. Microanalysisfound: C, 69.91; H, 6.57; N, 15.67. C₂₆H₂₉N₅O₂; 0.2H₂O requires C,69.84; H, 6.63; N, 15.66%. 10 (b)

A 83 white solid ¹H-nmr(DMSO-d₆, 400 MHz) δ: 0.62(m, 2H), 0.94(m, 2H),1.40(m, 2H), 1.80(m, 2H), 2.16(m, 2H), 2.62(m, 2H), 2.96(m, 2H), 3.16(m,1H), 3.20(s, 3H), 3.50(s, 2H), 3.78(s, 3H), 3.96(m, 2H), 4.22(m, 1H),4.78(s, 2H), 6.18(m, 1H), 6.56(bs, 1H), 7.24(d, 1H), 7.58(d, 1H), #11.00(bs, 1H). LRMS: m/z(ES⁺) 477[MH⁺]. Microanalysis found: C, 67.22;H, 6.96; N, 14.40. C₂₇H₃₃N₅O₃; 0.5C₂H₅OH requires C, 67.45; H, 7.28; N,14.05%. 11 (a)

A 44 white solid ¹H-nmr(DMSO-d₆, 400 MHz) δ: 0.65(m, 2H), 0.91(m, 2H),2.38(m, 4H), 2.93(t, 2H), 3.51(m, 3H), 3.55(m, 4H), 3.76(s, 3H), 3.92(t,2H), 4.77(s, 2H), 6.14(s, 1H), 6.52(s, 1H), 7.27(d, 1H), 7.56(d, 1H),11.58(bs, 1H). LRMS: m/z(ES⁺) 470[MNa⁺]. # Microanalysis found: C,66.29; H, 6.50; N, 15.48. C₂₅H₂₉N₅O₃; 0.3H₂O requires C, 66.29; H, 6.59;N, 15.46%.

EXAMPLE 115-Cyclopropyl-7-methoxy-2-(2-morpholin-4-ylmethyl-7,8-dihydro[1,6]-naphthyridin-6(5H)-yl)-4(3H)-quinazolinone

[1172]

[1173] A mixture of the chloride from preparation 18 (351 mg, 1.4 mmol)in n-butanol (21 mL), the amine from preparation 106 (335 mg, 1.43 mmol)and N,N-diisopropylethylamine (633 mg, 4.9 mmol) was heated under refluxfor 6 hours, then a further 7 hours at room temperature. The resultingprecipitate was filtered off, washed with n-butanol, and dried in vacuo.The solid was purified by column chromatography on silica gel using an15 elution gradient of dichloromethane:methanol (97:3 to 93:7), and theproduct triturated with ether to afford the title compound as a whitesolid, 470 mg.

[1174]¹H-nmr (DMSO-d₆, 400 MHz) δ: 0.65 (m, 2H), 0.91 (m, 2H), 2.38 (m,4H), 2.93 (t, 2H), 3.51 (m, 3H), 3.55 (m, 4H), 3.76 (s, 3H), 3.92 (t,2H), 4.77 (s, 2H), 6.14 (s, 1H), 7.27 (d, 1H), 7.56 (d, 1H), 11.58 (bs,1H). LRMS: m/z (ES⁺) 470 [MNa⁺].

[1175] Microanalysis found: C, 66.29; H, 6.50; N, 15.48.C₂₅H₂₉N₅O₃;0.3H₂O requires C, 66.29; H, 6.59; N, 15.46%.

EXAMPLES 12 to 25

[1176]

[1177] General Method

[1178] To a solution of the chloro-quinazolinone from preparation 18 (1eq) in n-butanol (15 mL per mmol) under nitrogen was addeddiisopropylethylamine (A) or triethylamine (B) (1.7-8.0 eq) and theappropriate secondary amine (1-2 eq). The resultant mixture was thenheated at reflux for 1-6 hours, cooled and the product was isolated byfiltration, washing with n-butanol and diethyl ether. Ex. no. R BaseYield %/Form Spectroscopic and Analytical Data 12

A 66 solid ¹H-nmr(DMSO-d₆, 400 MHz) δ: 0.66(m, 2H), 0.93(m, 2H), 1.59(d,1H), 1.80(d, 1H), 2.45(d, 1H), 2.76(d, 1H), 2.94(t, 2H), 3.47(s, 1H),3.52(d, 2H), 3.77(m, 5H), 3.91(d, 1H), 3.95(t, 2H), 4.33(s, 1H), 4.78(s,2H), 6.14(d, 1H), 6.53(d, 1H), 7.29(d, 1H), 7.56(d, 1H), # 11.09(bs,1H). LRMS: m/z(ES⁺) 460[MH⁺]. Microanalysis found: C, 67.96; H, 6.38; N,15.12. C₂₆H₂₉N₅O₃ requires C, 67.67; H, 6.38; N, 15.12%. 13

B solid ¹H-nmr(CDCl₃, 400 MHz) δ: 0.70(m, 2H), 1.00(m, 2H), 2.96(t, 2H),3.38(m, 1H), 3.48(m, 4H), 3.79(m, 4H), 3.83(s, 3H), 3.94(t, 2H), 4.69(s,2H), 6.29(s, 1H), 6.51(d, 1H), 6.64(s, 1H), 7.30(d, 1H), 9.22(bs, 1H).LRMS: m/z(ES⁺) 456[MNa⁺] 14 (a)

A 62 solid ¹H-nmr(CDCl₃, 400 MHz) δ: 0.71(m, 2H), 0.99(m, 2H), 2.34(s,3H), 2.51(m, 4H), 2.97(t, 2H), 3.38(m, 1H), 3.43(m, 4H), 3.82(s, 3H),3.98(t, 2H), 4.73(s, 2H), 6.27(s, 1H), 6.52(d, 1H), 6.64(s, 1H), 7.24(m,1H), 9.60(bs, 1H). LRMS: m/z(ES⁺) 469[MNa⁺] 15

A 86 off-white solid ¹H-nmr(CDCl₃, 400 MHz) δ: 0.72(m, 2H), 1.00(m, 2H),2.63(t, 2H), 3.37(m, 1H), 3.85(s, 3H), 3.97(t, 2H), 4.39(bs, 2H),4.73(s, 2H), 6.31(d, 1H), 6.52(m, 3H), 6.66(d, 1H), 7.92(d, 1H). LRMS:m/z(ES⁺) 364[MH⁺] 16

A 66 solid ¹H-nmr(CDCl₃, 400 MHz) δ: 0.74(m, 2H), 0.98(m, 2H), 2.24(s,6H), 3.09(m, 2H), 3.42(m, 1H), 3.54(s, 2H), 3.86(s, 3H), 4.01(t, 2H),4.90(s, 2H), 6.31(d, 1H), 6.68(d, 1H), 7.01(d, 1H), 8.36(d, 1H),10.96(bs, 1H). LRMS: m/z(ES⁺) 406[MH⁺]. # Microanalysis found: C, 67.92;H, 6.73; N, 17.23. C₂₃H₂₇N₅O_(2 requires C, 68.13; H, 6.71; N, 17.27%.)17

B 50 white solid ¹H-nmr(CDCl₃, 400 MHz) δ: 0.63(m, 2H), 0.91(m, 2H),0.98(d, 6H), 1.97(s, 3H), 2.80(m, 1H), 3.00(m, 2H), 3.51(m, 1H), 3.61(s,2H), 3.77(s, 3H), 3.85(t, 2H), 4.78(s, 2H), 6.15(s, 1H), 6.54(s, 1H),7.13(d, 1H), 8.22(d, 1H), 11.12(bs, 1H). # LRMS: m/z(ES⁻) 432[M − H⁻].Microanalysis found: C, 68.41; H, 7.23; N, 15.76. C₂₅H₃₁N₅O₂; 0.25H₂Orequires C, 68.55; H, 7.25; N, 15.99%. 18

B 61 white solid ¹H-nmr(CDCl₃, 400 MHz) δ: 0.74(m, 2H), 0.98(m, 2H),1.26(d, 4H), 1.77(m, 4H), 3.19(m, 4H), 3.41(m, 1H), 3.65(s, 2H), 3.86(s,3H), 3.97(t, 2H), 4.89(s, 2H), 6.31(d, 1H), 6.67(d, 1H), 7.01(d, 1H),8.33(d, 1H), 10.44(bs, 1H). LRMS: m/z(ES⁻) 456[M − H⁻] # Microanalysisfound: C, 70.41; H, 6.80; N, 15.13. C₂₇H₃₁N₅O₂; 0.25H₂O requires C,70.18; H, 6.87; N, 15.16%. 19

A 38 white solid ¹H-nmr(CDCl₃, 400 MHz) δ: 0.73(m, 2H), 0.99(m, 2H),1.25(s, 1H), 1.85(m, 2H), 2.16(m, 3H), 2.70(m, 2H), 3.12(t, 2H), 3.20(m,1H), 3.31(s, 3H), 3.40(m, 1H), 3.62(s, 2H), 3.85(s, 3H), 3.93(t, 2H),4.87(s, 2H), 6.32(d, 1H), 6.88(d, 1H), 7.02(d, 1H), 8.36(d, 1H). # LRMS:m/z(ES⁺) 476[MH⁺]Microanalysis found: C, 66.97; H, 7.00; N, 14.19.C₂₇H₃₃N₅O₃; 0.50H₂O requires C, 66.92; H, 7.07; N, 14.45%. 20 (a)

B 91 white solid ¹H-nmr(CDCl₃, 400 MHz) δ: 0.76(m, 2H), 0.99(m, 2H),2.47(m, 4H), 3.11(t, 2H), 3.43(m, 1H), 3.64(s, 2H), 3.67(m, 4H), 3.87(s,3H), 4.01(t, 2H), 4.92(s, 2H), 6.32(s, 1H), 6.68(s, 1H), 7.04(d, 1H),8.37(d, 1H), 10.78(bs, 1H). LRMS: m/z(ES⁺) 448[MH⁺] # Microanalysisfound: C, 66.60; H, 6.51; N, 15.63. C₂₅H₂₉N₅O₃; 0.20H₂O requires C,66.56; H, 6.59; N, 15.52%. 21 (a)

A 25 yellow oil ¹H-nmr(CDCl₃, 400 MHz) δ: 0.78(m, 2H), 1.00(m, 2H),1.52-1.80(m, 4H), 1.98(m, 1H), 2.78(m, 1H), 2.98(m, 1H), 3.18(m, 2H),3.42(m, 1H), 3.63(m, 1H), 3.90(s, 3H), 4.00(m, 2H), 4.17(m, 1H), 4.42(m,1H), 4.90(s, 2H), 6.35(d, 1H), 6.67(d, 1H), 7.02(d, 1H), 8.37(d, 1H). #LRMS: m/z(ES⁻) 458[M − H-]. Microanalysis found: C, 67.48; H, 6.40; N,15.10. C₂₆H₂₉N₅O₃; requires C, 67.96; H, 6.36; N, 15.24%. 22 (a)

A 54 off-white solid ¹H-nmr(CDCl₃, 400 MHz) δ: 0.73(m, 2H), 1.00(m, 2H),1.78(m, 4H), 2.57(m, 4H), 3.04(t, 2H), 3.45(m, 1H), 3.72(s, 2H), 3.85(s,3H), 4.08(t, 2H), 4.98(s, 2H), 6.34(d, 1H), 6.68(d, 1H), 8.95(s, 1H),11.32(bs, 1H). LRMS: m/z(ES⁺) 433[MH⁺]. # Microanalysis found: C, 66.23;H, 6.50; N, 19.21. C₂₄H₂₈N₆O₂ requires C, 66.65; H, 6.53; N, 19.43%. 23

A 38 white solid ¹H-nmr(CDCl₃, 400 MHz) δ: 0.73(m, 2H), 0.99(m, 2H),1.42(m, 2H), 1.54(m, 4H), 2.40(m, 4H), 3.09(t, 2H), 3.43(m, 1H), 3.54(s,2H), 3.85(s, 3H), 4.05(t, 2H), 4.96(s, 2H), 6.34(d, 1H), 6.67(d, 1H),8.94(s, 1H), 10.85(bs, 1H). LRMS: m/z(ES⁺) 447[MH⁺]. # Microanalysisfound: C, 66.96; H, 6.82; N, 18.63. C₂₅H₃₀N₆O₂ requires C, 67.24; H,6.77; N, 18.82%. 24

A 73 solid ¹H-nmr(CDCl₃, 400 MHz) δ: 0.73(m, 2H), 1.01(m, 2H), 1.55(m,2H), 1.84(m, 2H), 2.23(m, 2H), 2.71(m, 2H), 3.07(t, 2H), 3.22(m, 1H),3.31(s, 3H), 3.42(m, 1H), 3.57(s, 2H), 3.85(s, 3H), 4.06(t, 2H), 4.97(s,2H), 6.34(d, 1H), 6.67(d, 1H), 8.94(s, 1H), 10.96(bs, 1H). # LRMS:m/z(ES⁺) 477[MH⁺]. Microanalysis found: C, 63.66; H, 6.62; N, 17.13.C₂₆H₃₂N₆O₃; 0.75H₂O requires C, 63.72; H, 6.89; N, 17.15%. 25

A 59 white solid ¹H-nmr(CDCl₃, 400 MHz) δ: 0.74(m, 2H), 1.00(m, 2H),2.79(s, 6H), 3.36(m, 1H), 3.85(s, 3H), 3.95(t, 2H), 4.09(t, 2H), 4.89(s,2H), 6.34(d, 1H), 6.56(s, 1H), 6.65(d, 1H), 10.81(bs, 1H). LRMS:m/z(ES⁺) 381[MH⁺]. Microanalysis found: C, 61.81; H, 6.25; N, 21.47. #C₂₀H₂₄N₆O₂; 0.5H₂O requires C, 61.68; H, 6.47; N, 21.58%.

EXAMPLE 265-Cyclopropyl-7-methoxy-2-(2-(1-piperidinylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4(3H)-quinazolinone

[1179]

[1180] A mixture of the chloride from preparation 18 (302 mg, 1.2 mmol),the amine from preparation 124 (1.23 mmol) and diisopropylethylamine(646 mg, 5 mmol) in n-butanol (10 mL) was heated under reflux for 1.5hours. The cooled mixture was diluted with water and extracted withdichloromethane (3×50 mL). The combined organic extracts were dried(MgSO₄) and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel using an elution gradient ofdichloromethane:methanol (100:0 to 90:10) to afford the title compoundas an off-white solid, 307 mg.

[1181]¹H-nmr (CDCl₃, 400 MHz) δ: 0.72 (m, 2H), 0.96 (m, 2H), 1.48 (m,2H), 1.71 (m, 4H), 2.70 (m, 4H), 3.07 (t, 2H), 3.53 (m, 1H), 3.84 (s,3H), 3.88 (bs, 2H), 4.06 (t, 2H), 4.89 (s, 2H), 6.31 (s, 1H), 6.66 (s,1H), 8.51 (s, 1H), 11.12 (bs, 1H).

[1182] LRMS: m/z (ES⁺) 447 [MH⁺]

[1183] Microanalysis found: C, 65.74; H, 6.83; N, 18.28.C₂₅H₃₀N₆O₂;0.5H₂O requires C, 65.91; H, 6.86; N, 18.45%.

EXAMPLE 272-(3-Amino-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-5-cyclopropyl-7-methoxy-4(3H)-quinazolinone

[1184]

[1185] The title compound was obtained as a yellow solid in 23% yield,from the chloride from preparation 18 and the amine from preparation136, following a similar procedure to that described in example 26,except dichloromethane:methanol:0.88 ammonia (90:10:1) was used as thecolumn eluant.

[1186]¹H-nmr (DMSOd₆, 400 MHz) δ: 0.64 (m, 2H), 0.2 (m, 2H), 3.48 (m,1H), 3.75 (m, 5H), 3.93 (t, 2H), 4.68 (s, 2H), 5.48 (s, 2H), 6.16 (s,1H), 6.28 (s, 1H), 6.53 (s, 1H), 11.10 (bs, 1H).

[1187] LRMS: m/z (ES⁺) 353 [MH⁺]

EXAMPLE 285-Cyclopropyl-7-methoxy-2-(3-[(2-methoxyethyl)(methyl)amino]-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-4(3H)-quinazolinone

[1188]

[1189] The title compound was obtained as a white solid in 45% yield,from the chloride from preparation 18 and the amine from preparation133, following a similar procedure to that described in example 26.

[1190]¹H-nmr (CDCl₃, 400 MHz) δ: 0.73 (m, 2H), 0.96 (m, 2H), 2.82 (s,3H), 3.21 (t, 2H), 3.49 (m, 1H), 3.50 (s, 3H), 3.51 (t, 2H), 3.84 (s,3H), 3.96 (t, 2H), 4.09 (t, 2H), 4.91 (s, 2H), 6.33 (d, 1H), 6.55 (s,1H), 6.65 (d, 1H), 11.38 (bs, 1H).

[1191] LRMS: m/z (ES⁺) 425 [MH⁺]

EXAMPLE 295-Cyclopropyl-2-(3-ethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-7-methoxy-4(3H)-quinazolinone

[1192]

[1193] The title compound was obtained as a white solid in 43% yield,from the chloride from preparation 18 and the amine from preparation131, following a similar procedure to that described in example 26,except dichloromethane:methanol:0.88 ammonia (95:50.5) was used as thecolumn eluant.

[1194]¹H-nmr (DMSOd₆, 400 MHz) δ: 0.62 (m, 2H), 0.96 (m, 2H), 1.16 (t,3H), 2.52 (m, 2H), 3.50 (m, 1H), 3.78 (s, 3H), 3.92 (m, 2H), 4.04 (m,2H), 4.78 (s, 2H), 6.18 (s, 1H), 6.56 (s, 1H), 6.60 (s, 1H), 10.80,11.25 (2×bs, 1H).

[1195] LRMS: m/z (ES⁺) 366 [MH⁺]

[1196] Microanalysis found: C, 64.26; H, 6.31; N, 18.10.C₂₀H₂₃N₅O₂;0.15CH₂Cl₂ requires C, 64.00; H, 6.21; N, 18.52%.

EXAMPLE 305-Cyclopropyl-7-methoxy-2-(5-(1-methyl-4-piperidinyl)-3,4-dihydro[2,6]naphthyridin-2(1H)-yl)-4(3H)-quinazolinone

[1197]

[1198] A mixture of the chloride from preparation 18 (0.40 mmol), theamine hydrochloride from preparation 120 (145.6 mg, 0.48 mmol) andtriethylamine (223 μl, 1.60 mmol) in n-butanol (6 mL) was heated underreflux for 3 hours. The cooled mixture was concentrated under reducedpressure and the residue partitioned between water (4 mL) with saturatedsodium bicarbonate solution (2 mL), and dichloromethane (30 mL), and thelayers separated. The aqueous phase was extracted with furtherdichloromethane (2×20 mL), and the combined organic solutions dried(MgSO₄) and evaporated under reduced pressure. The residual solid waspurified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol:0.88 ammonia (95:5:0.2 to90:10:0.6) to afford the title compound as a white solid, 110 mg.

[1199]¹H-nmr (DMSOd₆, 400 MHz) δ: 0.64 (m, 2H), 0.93 (m, 2H), 1.60 (m,2H), 1.83 (m, 2H), 2.04 (m, 2H), 2.21 (s, 3H), 2.80 (m, 1H), 2.87 (m,4H), 3.40 (m, 1H), 3.76 (s, 3H), 3.89 (t, 2H), 4.77 (s, 2H), 6.15 (s,1H), 6.51 (d, 1H), 7.04 (d, 1H), 8.30 (d, 1H), 11.07 (bs, 1H).

[1200] LRMS: m/z (ES⁺) 446 [MH⁺]

[1201] Microanalysis found: C, 68.43; H, 7.11; N, 15.35.C₂₆H₃₁N₅O₂;0.6H₂O requires C, 70.09; H, 7.11; N, 15.35%.

EXAMPLE 315-Cyclopropyl-2-(3-isopropyl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-7-methoxy-4(3H)-quinazolinoneand EXAMPLE 325-Cyclopropyl-2-(3-(1-hydroxy-1-methylethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-7-methoxy-4(3H)-quinazolinone

[1202]

[1203] A mixture of the chloride from preparation 18 (80 mg, 0.32 mmol),the amines from preparations 120 and 121 (99 mg), and triethylamine(178μl, 1.28 mmol) in n-butanol (6 mL) was heated under reflux for 3.5hours. The cooled mixture was concentrated under reduced pressure andthe solid residue partitioned between dichloromethane (30 mL) and asolution of saturated sodium bicarbonate (1 mL) in water (5 mL), and thephases separated. The aqueous layer was extracted with dichloromethane(2×30 mL), and the combined organic extracts dried (MgSO₄) andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel using an elution gradient ofdichloromethane:methanol (100:0 to 95:5) to afford the title compound ofexample 31, 42 mg.

[1204]¹H-nmr (CD₃OD, 400 MHz) δ: 0.65 (m, 2H), 0.97 (m, 2H), 1.28 (d,6H), 3.10 (m, 1H), 3.33 (s, 1H), 3.82 (s, 3H), 4.07 (m, 2H), 4.13 (t,2H), 4.84 (s, 2H), 6.34 (d, 1H), 6.75 (s, 1H);

[1205] LRMS: m/z (ES⁺) 380 [MH⁺]; Microanalysis found: C, 65.77; H,6.69; N, 18.46. C₂₁H₂₅N₅O₂;0.2H₂O requires C, 65.84; H, 6.68; N, 18.28%.

[1206] Further elution gave the title compound of example 32, 40 mg.

[1207]¹H-nmr (CD₃OD, 400 MHz) δ: 0.62 (m, 2H), 0.97 (m, 2H), 1.56 (s,6H), 3.29 (m, 1H), 3.82 (s, 3H), 4.00 (m, 2H), 4.53 (m, 2H), 4.84 (s,2H), 6.34 (s, 1H), 6.70 (s, 1H), 6.75 (s, 1H); LRMS: m/z (ES⁺) 396[MH⁺]; Microanalysis found: C, 63.12; H, 6.59; N, 17.21.C₂₁H₂₅N₅O₃;0.07CH₂Cl₂ requires C, 63.05; H, 6.31; N, 17.44%.

EXAMPLE 335-Cyclobutyl-7-methoxy-2-(2-(4-morpholinylmethyl)-7,8-dihydro[1,6]naphthyridin-6(5H)-yl)-4(3H)-quinazolinone

[1208]

[1209] The title compound was obtained as a solid in 74% yield from thecompounds from preparation 19 and 106, following the procedure describedin example 4.

[1210]¹H-nmr (DMSOd₆, 400 MHz) D: 1.66-1.75 (m, 1H), 1.83-2.03 (m, 3H),2.29 (m, 2H), 2.38 (m, 4H), 2.93 (t, 2H), 3.51 (s, 2H), 3.56 (m, 4H),3.81 (s, 3H), 3.92 (t, 2H), 4.57 (m, 1H), 4.77 (s, 2H), 6.59 (s, 2H),7.27 (d, 1H), 7.57 (d, 1H), 11.05 (bs, 1H).

[1211] LRMS : m/z (ES⁺) 462 [MH⁺]

[1212] Microanalysis found: C, 67.66; H, 6.78; N, 14.95. C₂₆H₃₁N₅O₃requires C, 67.66; H, 6.77; N, 15.17%.

EXAMPLE 345-Cyclohexyl-7-methoxy-2-(2-(4-morpholinylmethyl)-7,8-dihydro[1,6]naphthyridin-6(5H)-yl)-4(3H)-quinazolinone

[1213]

[1214] The title compound was obtained as a solid in 70% yield, afterrecrystallisation from diethyl ether, from the compounds frompreparation 20 and 106, following a similar procedure to that describedin example 26.

[1215]¹H-nmr (DMSOd₆, 400 MHz) δ: 1.15-1.46 (m, 5H), 1.66-1.84 (m, 5H),2.38 (m, 4H), 2.94 (t, 2H), 3.52 (s, 2H), 3.57 (m, 4H), 3.79 (s, 3H),3.93 (t, 2H), 4.14 (t, 1H), 4.77 (s, 2H), 6.57 (m, 2H), 7.27 (d, 1H),7.57 (d, 1H), 11.03 (bs, 1H).

[1216] LRMS: m/z (APCI⁺) 490 [MH⁺]

[1217] Microanalysis found: C, 68.84; H, 7.33; N, 14.18. C₂₈H₃₅N₅O₃requires C, 68.69; H, 7.21; N, 14.30%.

EXAMPLES 35 to 39

[1218]

[1219] The following examples were prepared following the proceduredescribed for examples 2 to 25. The compounds were then dissolved in asolution of dichloromethane with a minimum volume of methanol, thentreated with 1N ethereal hydrochloric acid. The resultant mixture wasevaporated under reduced pressure to afford the title compounds. Ex. no.R Base Yield %/Form Spectroscopic and Analytical Data 35

A 90 ¹H-nmr(DMSO-d₆, 400 MHz) δ: 0.76(m, 2H), 0.98(m, 2H), 3.18-3.35(m,7H), 3.79(s, 3H), 3.88(s, 4H), 4.00(m, 2H), 4.16(s, 2H), 4.98(s, 2H),6.38(s, 1H), 7.32(bs, 2H), 7.46(bs, 1H), 7.64(bs, 1H), 11.47(bs, 1H);LRMS(ES⁺): m/z(MH⁺) 447; # Microanalysis: Found: C, 58.41; H, 6.57; N,10.02. C₂₆H₃₀N₄O₃; 2HCl; H₂O requires C, 58.10; H, 6.38; N, 10.42% 36(a)

A 56 ¹H-nmr(DMSO-d₆, 400 MHz) δ: 0.74(m, 2H), 0.98(m, 2H), 3.10(m, 2H),3.22(m, 3H), 3.32(m, 1H), 3.80(s, 3H), 3.92(m, 1H), 4.00-4.44(m, 9H),5.02(s, 2H), 6.38(s, 1H), 7.33(d, 1H), 7.45(m, 2H), 11.50(bs, 1H);LRMS(ES⁺): m/z(MH⁺) 447; # Microanalysis: Found: C, 59.36; H, 6.28; N,10.53. C₂₆H₃₀N₄O₃; 2HCl; 0.4H₂O requires C, 59.29; H, 6.28; N, 10.64%.37 (b)

B 92 ¹H-nmr(DMSO-d₆, 400 MHz) δ: 0.71(m, 2H), 0.97(m, 2H), 3.26(t, 2H),3.38(m, 1H), 3.74(s, 3H), 4.12(t, 2H), 5.08(s, 2H), 6.35(s, 1H),7.07(bs, 1H), 7.75(dd, 1H), 8.20(m, 1H), 8.66(d, 1H). LRMS m/z: (ES⁻)347(M − H⁻) 38 (a)

A 42 white solid ¹H-nmr(DMSO-d₆, 400 MHz) δ: 0.72(m, 2H), 0.99(m, 2H),1.97(m, 4H), 3.00(m, 2H), 3.26-3.46(m, 5H), 3.80(s, 3H), 4.17 (m, 2H),4.61(s, 2H), 5.12(s, 2H), 6.38(s, 1H), 7.28(bs, 1H), 7.57(bs, 1H),8.46(d, 1H), 10.56(bs, 1H). LRMS m/z: (ES⁺) 432(MH⁺) 39

A 71 white solid ¹H-nmr(DMSO-d₆, 400 MHz) δ: 0.74(m, 2H), 0.97(m, 2H),1.55(m, 2H), 1.82(m, 4H), 3.03(t, 2H), 3.16-3.38(m, 5H), 3.80(s, 3H),4.16(t, 2H), 4.50(s, 2H), 5.17(s, 2H), 6.38(s, 1H), 7.32(d, 1H),7.62(bs, 1H), 8.49(d, 1H), 10.04(bs, 1H). LRMS m/z: (ES⁺) 446(MH⁺) #Microanalysis found: C, 58.21; H, 6.58; N, 13.05. C₂₆H₃₁N₅O₂; 2HCl; H₂Orequires C, 58.32; H, 6.63; N, 12.79%.

EXAMPLE 405-Cyclopropyl-2-(2-[(dimethylamino)methyl]-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-7-methoxy-4(3H)-quinazolinonedihydrochloride

[1220]

[1221] A mixture of the chloride from preparation 18 (60 mg, 0.24 mmol),the amine hydrochloride from preparation 121 (80 mg, 0.30 mmol) anddiisopropylethylamine (258 mg, 2 mmol) in n-butanol (4 mL) was heatedunder reflux for 1.5 hours. The cooled mixture was poured into water andextracted with dichloromethane (3×50 mL). The combined organic extractswere dried (MgSO₄) and evaporated under reduced pressure. The residuewas purified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol (100:0 to 80:20). The product wasre-dissolved in dichloromethane treated with 1 N ethereal hydrochloricacid (2 mL), and the solution evaporated under reduced pressure toafford the title compound as a light brown solid, 60 mg. ¹H-nmr (DMSO-d₆400 MHz) δ: 0.72 (m, 2H), 0.97 (m, 2H), 2.87 (s, 6H), 3.14 (m, 2H), 3.36(m, 1H), 3.79 (s, 3H), 4.18 (m, 2H), 4.56 (s, 2H), 5.13 (s, 2H), 6.38(s, 1H), 7.42 (bs, 1H), 8.71 (s, 1H), 10.49 (bs, 1H).

[1222] LRMS: m/z (ES⁺) 407 [MH⁺]

[1223] Microanalysis: Found: C, 54.11; H, 5.94; N, 16.83.C₂₂H₂₆N₆O₂;2HCl;0.5H₂O requires C,54.10; H, 5.98; N, 17.21%

EXAMPLES 41 to 43

[1224] The following examples of general structure:

[1225] were prepared from the chloride from preparation 18, theappropriate amines and diisopropylethylamine, following a similarprocedure to that described in example 40. Ex. no. R Yield %/FormSpectroscopic and Analytical Data 41

63 off-white solid ¹H-nmr(DMSOd₆, 400 MHz) δ: 0.68(m, 2H), 0.95(m, 2H),1.85-2.05(m, 4H), 3.05(t, 2H), 3.15(m, 2H), 3.43(m, 1H), 3.60(m, 2H),3.75(s, 3H), 4.05(m, 2H), 4.65(d, 2H), 4.95(s, 2H), 6.25(s, 1H),6.85(bs, 1H), 8.73(s, 1H), 10.45(bs, 1H). LRMS: m/z(ES⁺) 433[MH⁺] 42 (a)

86 white solid ¹H-nmr(CD₃OD, 400 MHz) δ: 0.77(m, 2H), 1.07(m, 2H),2.66(s, 3H), 3.10(m, 1H), 3.91(s, 3H), 4.34(t, 2H), 4.43(t, 2H), 5.16(s,2H), 6.64(d, 1H), 7.11(s, 1H), 7.46(s, 1H). LRMS: m/z(ES⁺) 352[MH⁺]. #Microanalysis: Found: C, 54.19; H, 5.77; N, 16.28. C₁₉H₂₁N₅O₂; 2HClrequires C, 53.78; H, 5.46; N, 16.50% 43 (a)

78 yellow foam ¹H-nmr(CD₃OD, 400 MHz) δ: 0.78(m, 2H), 1.09(m, 2H),1.41(t, 3H), 3.04(m, 3H), 3.92(s, 3H), 4.35(t, 2H), 4.46(t, 2H), 5.18(s,2H), 6.65(s, 1H), 7.12(s, 1H), 7.49(s, 1H). LRMS: m/z(ES⁺) 366[MH⁺]. #Microanalysis: Found: C, 53.58; H, 5.97; N, 15.27. C₂₀H₂₃N₅O₂; 2HClrequires C, 53.48; H, 5.88; N, 15.59%

EXAMPLE 445-Cyclopropyl-2-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-7-methoxy-4(3H)-quinazolinonedihydrochloride

[1226]

[1227] A mixture of the chloride from preparation 18 (70 mg, 0.28 mmol),the amine hydrochloride from preparation 129 (66 mg, 0.34 mmol) andtriethylamine (113 μl, 1.1 2 mmol) in n-butanol (6 mL) was heated underreflux for 6 hours. The cooled mixture was concentrated under reducedpressure and the residual solid partitioned between water (5 mL) anddichloromethane:methanol (95:5, 50 mL) and the layers separated. Theaqueous phase was extracted with dichloromethane:methanol (95:5, 2×30mL), and the combined organic solutions dried (MgSO₄) and evaporatedunder reduced pressure. The product was purified by columnchromatography on silica gel using an elution gradient ofdichloromethane:methanol (98:2 to 90:10) to give a white solid. This wassuspended in water, diluted with saturated sodium bicarbonate solution,and extracted with dichloromethane (3×50 mL). The combined organicextracts were dried (MgSO₄) and evaporated under reduced pressure. Thesolid was dissolved in dichloromethane:methanol (1:1, 8 mL), 1N etherealhydrochloric acid added, and the mixture evaporated under reducedpressure to afford the title compound as a foam, 69 mg.

[1228]¹H-nmr (DMSOd₆, 400 MHz) δ: 0.74 (m, 2H), 0.99 (m, 2H), 3.25 (m,1H), 3.81 (s, 3H), 4.20 (t, 2H), 4.46 (t, 2H), 5.10 (s, 2H), 6.42 (s,1H), 7.01 (s, 1H), 7.64 (s, 1H), 9.15 (s, 1H).

[1229] LRMS: m/z (ES⁺) 338 [MH⁺]

[1230] Microanalysis found: C, 52.78; H, 5.46; N, 16.82. C₁₈H₁₉N₅O₂;2HClrequires C, 52.69; H, 5.16; N, 17.07%

EXAMPLE 455-Cyclopropyl-7-methoxy-2-(2-{[(2-methoxyethyl)(methyl)amino]methyl}-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4(3H)-guinazolinonehydrochloride

[1231]

[1232] A mixture of the chloride from preparation 18 (140 mg, 0.5 mmol),the amine hydrochloride from preparation 122 (290 mg, 0.84 mmol) andtriethylamine (390 μl, 2.8 mmol) in n-butanol (3mL) was heated underreflux for 1.5 hours. The cooled mixture was filtered, the resultingsolid washed with n-butanol and diethyl ether, then dried at 60° C. invacuo, to afford the title compound as a cream solid.

[1233]¹H-nmr (CDCl₃, 400 MHz) δ: 0.73 (m, 2H), 0.97 (m, 2H), 2.41 (s,3H), 2.75 (t, 2H), 3.08 (t, 2H), 3.33 (s, 3H), 3.38 (m, 1H), 3.56 (t,2H), 3.86 (m, 5H), 4.10 (t, 2H), 4.92 (s, 2H), 6.33 (s, 1H), 6.68 (s,1H), 8.51 (s, 1H), 11.12 (bs, 1H).

[1234] LRMS: m/z (ES⁻) 449 [M-H⁻]

[1235] Microanalysis found: C, 58.44; H, 6.16; N, 16.97.C₂₄H₃₀N₆O₃;HCl;0.3H₂O requires C, 58.54; H, 6.47; N, 17.07%.

EXAMPLE 465-Cyclopropyl-7-methoxy-2-(2-{[2-(4-morpholinyl)ethoxy]methyl}-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4(3H)-guinazolinonehydrochloride

[1236]

[1237] The title compound was obtained as a cream solid in 65% yield,from the chloride from preparation 18 and the amine hydrochloride frompreparation 125, following a similar procedure to that described inexample 45, except, diisopropylethylamine was used instead oftriethylamine.

[1238]¹H-nmr (CDCl₃, 400 MHz) δ: 0.85 (m, 2H), 00.97 (m, 2H), 2.50 (m,4H), 2.67 (m, 2H), 3.09 (m, 2H), 3.38 (m, 1H), 3.65 (m, 4H), 3.74 (t,2H), 3.83 (s, 3H), 4.15 (m , 2H), 4.72 (s, 2H), 4.91 (s, 2H), 6.35 (s,1H), 6.64 (s, 1H), 8.53 (s, 1H), 10.88 (bs, 1H),.

[1239] LRMS: m/z ES⁻) 491 [M-H⁻]

[1240] Microanalysis found: C, 58.71; H, 6.15; N, 15.65. C₂₆H₃₂N₆O₄;HClrequires C, 59.03; H, 6.29; N, 15.89%.

EXAMPLE 475-Cyclopropyl-7-methoxy-2-(3-morpholin-4-ylmethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3H-quinazolin-4-one

[1241]

[1242] The chloro compound from preparation 18 (100 mg, 0.4 mmol) wasmixed with the imidazopyrazine from preparation 173 (106 mg, 0.48 mmol)and triethylamine (167 μl, 1.2 mmol) in n-butanol (10 ml) under anitrogen atmosphere and the mixture was heated under reflux for 6 hours.The reaction mixture was cooled to room temperature and the solid formedwas isolated by filtration. The material obtained was washed withn-butanol (20 ml), diethyl ether (100 ml), water (20 ml) and diethylether (100 ml) and was then dried under vacuum at 80° C. for 4 hours togive the title compound (95 mg).

[1243]¹H-nmr (DMSOd₆ 400 MHz) δ: 1.65 (m, 2H), 1.94 (m, 2H), 2.34 (m,4H), 3.53 (m, 7H), 3.78 (s, 3H), 3.98 (m, 2H), 4.12 (m, 2H), 4.80 (s,2H), 6.19 (d, 1H), 6.57 (d, 1H), 6.59 (s, 1H), 11.20 (s, 1H)

[1244] LRMS: m/z (ES⁺) 459 [MNa⁺]

[1245] Microanalysis found: C, 62.38; H, 6.39; H, 18.95; C₂₃H₂₈N₆O₃ 0.25H₂O requires C, 62.29; H, 6.47; N, 19.25%

EXAMPLES 48 to 86

[1246] The compounds of the following tabulated examples of the generalformula:

[1247] were prepared by the general method outlined below using theappropriate chloro compound and cyclic amine.

[1248] To a solution of the chloro-quinazolinone (1 eq) in n-butanol (15ml per mmol) under nitrogen was added N,N-diisopropylethylamine ortriethylamine (1.7-8 eq) and the appropriate secondary amine (1-2 eq).The resultant mixture was then heated under reflux for 1-6 hours, cooledand the product was isolated by filtration, washing with n-butanol anddiethyl ether (Method a).

[1249] Some reaction mixtures were concentrated under reduced pressure,the residue partitioned between dichloromethane and water, the organicphase separated, dried (MgSO₄) and evaporated under reduced pressure(Method b).

[1250] Some products were additionally purified by column chromatographyon silica gel using dichloromethane: methanol or dichloromethane:methanol: 0.88 ammonia as eluants (Method c). Ex No. Yield (Method) R1R2 % Spectroscopic and analytical data 48 (b)

79 ¹H NMR(DMSOd₆, 400 MHz) δ: 0.66(m, 2H), 0.94(m, 2H), 0.35(m, 1H),3.77(s, 3H), 3.99(m, 2H), 4.12(m, 2H), 4.42(d, 2H), 4.82(s, 2H), 5.16(t,1H), 6.18(s, 1H), 6.56(s, 1H), 6.68(s, 1H). LRMS: m/z(ES⁺) 390[MNa⁺] #Microanalysis found: C, 61.32; H, 5.76; N, 18.48; C₁₉H₂₁N₅O₃ 0.25H₂Orequires; C, 61.36; H, 5.83; 18.83% 49^(D) (a)

58 ¹H NMR(DMSOd₆, 400 MHz) δ: 0.66(m, 2H), 0.95(m, 2H), 1.56(m, 2H),1.90(m, 2H), 2.79(m, 2H), 3.15(m, 2H), 3.25(s, 3H), 3.30(m, 1H), 3.50(m,1H), 3.77(s, 3H), 3.86(m, 2H), 3.93(m, 2H), 4.76(s, 2H), 6.16(s, 1H),6.47(s, 1H), 6.54(s, 1H), 11.10(s, 1H); # LRMS: m/z(ES⁺) 451[MH⁺];Microanalysis found: C, 63.65; 6.76; 18.40; C₂₄H₃₀N₆O₃ 0.1H₂O requires;C, 63.73; H, 6.73; N 18.58% 50^(D) (a)

74 ¹H NMR(DMSOd₆, 400 MHz) δ: 1.73(m, 1H), 1.96(m, 3H), 2.29(s, m, 2H),2.38(m, 4H), 2.93(t, 2H), 3.51(s, 2H), 3.56(m, 4H), 3.80(s, 3H), 3.92(t,2H), 4.51(m, 1H), 4.77(s, 2H), 6.59(s, 2H), 7.27(d, 1H), 7.57(d, 1H),11.05(s, 1H); LRMS: m/z(ES⁺) 485[MNa⁺] 51^(D) (a)

41 ¹H NMR(DMSOd₆, 400 MHz) δ: 1.15(d, 6H), 2.98(t, 2H), 3.80(s, 3H),3.94(t, 2H), 4.53(m, 1H), 4.80(s, 2H), 6.60(s, 2H), 7.20(m, 1H), 7.60(d,1H), 8.38(d, 1H), 10.91(s, 1H); LRMS: m/z(ES⁺) 451[MH⁺]; Microanalysis:Found: C, 68.42; H, 6.50; N, 15.66; # C₂₀H₂₂N₄O₂ requires; C, 68.55; H,6.33; N, 15.99%. M.p. 227-229° C. 52^(D) (a)

58 ¹H NMR(DMSOd₆, 400 MHz) δ: 1.16(d, 6H), 2.33(m, 4H), 2.95(t, 2H),3.42(s, 2H), 3.52(m, 4H), 3.79(s, 3H), 3.83(t, 2H), 4.55(m, 1H), 4.78(s,2H), 6.58(s, 2H), 7.10(m, 3H). LRMS: m/z(ES⁺) 449[MH⁺]. Microanalysis:Found: C, 69.62; H, 7.31; N, 12.19; # C₂₆H₃₂N₄O₃ requires; C, 69.62; H,7.19; 12.49%. M.p. 231-233° C. 53^(D) (a)

62 ¹H NMR(DMSOd₆, 400 MHz) δ: 1.16(d, 6H), 2.71(t, 2H), 3.80(s, 3H),3.86(t, 2H), 4.54(m, 5H), 6.40(d, 1H), 6.58(d, 2H), 6.81(s, 1H), 7.19(m,2H), 7.30(d, 1H), 7.67(m, 1H), 8.48(d, 1H), 10.84(s, 1H). LRMS: m/z(ES⁺)457[MH⁺]. # Microanalysis: Found: C, 68.21; H, 6.21; 18.21; C₂₆H₂₈N₆O₂requires C, 68.40; H, 6.18; N, 18.41% M.p. 227-229° C. 54¹ (a)

60 ¹H-NMR(DMSOd₆, 400 MHz) δ: 1.62(m, 1H), 1.79(m, 1H), 2.08(m, 2H),2.41(m, 2H), 2.90(t, 2H), 2.99(s, 3H), 3.79(m, 5H), 4.67(m, 1H), 4.76(s,2H), 5.95(d, 1H), 6.30(s, 1H), 7.11(d, 1H), 7.20(m, 2H). LRMS: m/z(ES⁺)471[MH⁺] 55 (b)

68 ¹H-NMR(DMSOd₆, 400 MHz) δ: 1.27(d, 6H), 2.95(s, 2H), 3.80(s, 3H),3.92(s, 2H), 4.54(m, 1H), 4.80(s, 2H), 6.20(s, 1H), 6.35(s, 1H), 7.20(m,1H), 7.59(d, 1H), 8.39(s, 1H). LRMS: m/z(ES⁺) 367[MH⁺]. Microanalysis:Found; C, 64.63; H, 5.99; N, 15.01; # C₂₀H₂₂N₄O₃ 0.25H₂O requires; C,64.76; H, 6.11; N, 15.10% 56 (a)

81 ¹H-NMR(DMSOd₆, 400 MHz) δ: 1.27(d, 6H), 2.72(t, 2H), 3.27(s, 3H),3.39(t, 2H), 3.44(m, 2H), 3.79(s, 3H), 3.85(t, 2H), 4.54(m, 3H), 6.18(s,1H), 6.21(s, 1H), 6.32(s, 1H), 6.39(d, 1H), 7.18(d, 1H), 10.60(s, 1H).LRMS: m/z(ES⁺) 440[MH⁺]. # Microanalysis: Found: C, 61.80; H, 6.62; N,15.31; C₂₃H₂₉N₅O₄ 0.4H₂O requires C, 61.84; H, 6.72; N, 15.68% 57² (a)

34 ¹H-NMR(DMSOd₆, 400 MHz) δ: 0.95(t, 6H), 1.65(m, 1H), 1.79(m, 1H),2.09(m, 2H), 2.44(m, 6H), 3.93(t, 2H), 3.48(s, 2H), 3.80(m, 2H), 4.69(t,2H), 4.77(s, 2H), 5.92(d, 1H), 6.29(d, 1H), 7.10(m, 3H). LRMS: m/z(ES⁺)463[MH⁺] 58 (a)

65 ¹H-NMR(DMSOd₆, 400 MHz) δ: 2.01(m, 1H), 2.17(m, 1H), 2.96(t, 2H),3.83(m, 9H), 4.79(s, 2H), 4.99(m, 1H), 6.14(s, 1H), 6.25(s, 1H), 7.20(m,1H), 7.60(d, 1H), 8.38(d, 1H), 10.70(s, 1H) LRMS: m/z(ES⁺) 417[MNa⁺] #Microanalysis: Found: C, 63.10; H, 5.72; N, 13.66; C₂₁H₂₂N₄O₄ 0.25H₂Orequires; C, 63.23; H, 5.68; N, 14.04% 59 (a)

82 ¹H-NMR(DMSOd₆, 400 MHz) δ: 2.02(m, 1H), 2.14(m, 1H), 2.72(t, 2H),3.26(s, 3H), 3.38(m, 2H), 3.42(m, 2H), 3.85(m, 9H), 4.56(s, 2H), 4.99(m,1H), 6.12(s, 1H), 6.21(s, 1H), 6.36(m, 2H), 7.18(d, 1H), 10.67(s, 1H).LRMS: m/z(ES⁺) 490[MNa⁺] # Microanalysis: Found: C, 61.05; H, 6.21; N,14.68; C₂₄H₂₉N₅O₅ 0.25H₂O requires; C, 61.07; H, 6.30; N, 14.84% 60 (a)

84 ¹H-NMR(DMSOd₆, 400 MHz) δ: 2.01(m, 1H), 2.15(m, 1H), 2.70(m, 2H),3.82(m, 9H), 4.53(d, 2H), 4.59(s, 2H), 4.99(m, 1H), 6.12,(s, 1H),6.23(s, 1H), 6.41(d, 1H), 6.83(s, 1H), 7.20(m, 2H), 7.32(d, 1H), 7.68(m,1H), 8.47(d, 1H), 10.55(s, 1H). # LRMS: m/z(ES⁺) 501[MH⁺].Microanalysis: Found: C, 63.97; H, 5.68; N, 16.28; C₂₇H₂₈N₆O₄ 0.4H₂Orequires; C 63.87; H, 5.68; N, 16.55% 61^(D) (a)

71 ¹H-NMR(DMSOd₆, 400 MHz) δ: 2.96(t, 2H), 3.36(s, 3H), 3.68(t, 2H),3.79(s, 3H), 3.94(t, 2H), 4.09(t, 2H), 4.80(s, 2H), 6.20(d, 1H), 6.32(s,1H), 7.20(m, 1H), 7.60(d, 1H), 8.38(d, 1H). LRMS: m/z(ES⁺) 383[MH⁺]. #Microanalysis: Found: C, 61.94; H, 5.80; N, 14.16; C₂₀H₂₂N₄O₄ 0.3H₂Orequires; C, 61.85; H, 5.88; N, 14.43% 62^(D) (a)

89 ¹H-NMR(DMSOd₆, 400 MHz) δ: 2.60(m, 2H), 3.37(s, 3H), 3.68(m, 2H),3.80(s, 3H), 3.92(m, 2H), 4.09(m, 2H), 4.66(s, 4H), 6.20(s, 1H), 6.33(s,1H), 6.40(d, 1H), 6.54(m, 1H), 7.15(m, 1H), 7.23(m, 1H), 7.63(m, 1H),6.75(d, 1H), 8.46(d, 1H). # LRMS: m/z(ES⁺) 489[MH⁺]. Microanalysis:Found: C, 63.41; H, 5.89; N, 16.67; C₂₆H₂₈N₆O₄ 0.25H₂O requires; C,63.34; H, 5.83; N, 17.04% M.p. 216-218° C. 63^(D) (c)

74 ¹H-NMR(DMSOd₆, 400 MHz) δ: 2.72(t, 2H), 3.26(s, 3H), 3.38(m, 5H),3.41(m, 2H), 3.68(t, 2H), 3.80(s, 3H), 3.85(t, 2H), 4.09(t, 2H), 4.55(s,2H), 6.19(s, 1H), 6.32(s, 1H), 6.36(d, 2H), 7.15(d, 1H) LRMS: m/z(ES⁺)456[MH⁺] # Microanalysis: Found: C, 60.44; H, 6.42; N, 15.27; C₂₃H₂₉N₅O₅requires; C, 60.65; H, 6.42; N, 15.37% 64^(D) (a)

92 ¹H-NMR(DMSOd₆, 400 MHz) δ: 2.69(t, 2H), 3.35(s, 3H), 3.69(t, 2H),3.80(s, 3H), 3.84(t, 2H), 4.09(t, 2H), 4.53(d, 2H), 4.58(s, 2H), 6.19(s,1H), 6.32(s, 1H), 6.41(d, 1H), 6.83(t, 1H), 7.20(m, 2H), 7.31(d, 1H),7.69(m, 1H), 8.48(d, 1H) # LRMS: m/z(ES⁺) 489[MH⁺]Microanalysis: Found:C, 63.35; H, 5.83; N, 17.84; C₂₆H₂₈N₆O₄ 0.25H₂O requires; C, 63.34; H,5.83; N, 17.04% 65^(D) (a)

75 ¹H-NMR(DMSOd₆, 400 MHz) δ: 0.40(m, 2H), 0.52(m, 2H), 1.21(m, 1H),2.95(t, 2H), 3.79(s, 3H), 3.88(d, 2H), 3.92(t, 2H), 4.79(s, 2H), 6.18(s,1H), 6.31(s, 1H), 7.20(m, 1H), 7.60(d, 1H), 8.35(d, 1H), 10.75(s, 1H).LRMS: m/z(ES⁺) 379[MH⁺]. # Microanalysis: Found: C, 66.34; H, 5.91; N,14.60; C₂₁H₂₂N₄O₃ requires; C, 66.65; H, 5.86; N, 14.80%. M.p. 191-193°C. 66^(D) (a)

76 ¹H-NMR(DMSOd₆, 400 MHz) δ: 0.39(d, 2H), 0.52(d, 2H), 1.22(m, 1H),2.60(m, 2H), 3.79(s, 3H), 3.89(d, 2H), 3.92(m, 2H), 4.66(s, 4H), 6.17(s,1H), 6.32(s, 1H), 6.39(d, 1H), 6.52(m, 1H), 7.18(m, 1H), 7.22(m, 1H),7.63(m, 1H), 7.74(d, 1H), 8.46(d, 1H). # LRMS: m/z(ES⁺) 485[MH⁺].Microanalysis: Found: C, 65.29; H, 5.96; N, 16.83; C₂₇H₂₈N₆O₃ 0.67H₂Orequires; C, 65.30; H, 5.95; N, 16.92%. M.p. 160-162° C. 67 (a)

86 ¹H-NMR(DMSOd₆, 400 MHz) δ: 0.38(d, 2H), 0.32(d, 2H), 1.20(m, 1H),2.69(t, 2H), 3.77(s, 3H), 3.83(m, 4H), 4.52(d, 2H), 4.56(s, 2H), 6.14(s,1H), 6.29(s, 1H), 6.40(d, 1H), 6.79(t, 1H), 7.19(d, 2H), 7.30(d, 1H),7.68(m, 1H), 7.47(d, 1H). LRMS: m/z(ES⁺) 485[MH⁺) # Microanalysis:Found: C, 66.60; H, 5.99; N, 16.93; C₂₇H₂₈N₆O₃ requires; C, 66.93; H,5.82; N, 17.34%. M.p. 204-206° C. 68 (a)

86 ¹H-NMR(DMSOd₆, 400 MHz) δ: 1.28(d, 6H), 2.72(s, 2H), 3.79(s, 3H),3.83(t, 2H), 4.54(m, 5H), 6.15(s, 1H), 6.33(s, 1H), 6.20(d, 1H), 6.85(s,1H), 7.20(d, 2H), 7.32(d, 1H), 7.70(m, 1H), 8.49(s, 1H), 10.63(s, 1H).LRMS: m/z(ES⁺) 473[MH⁺]. # Microanalysis: Found: C, 65.27; H, 6.07; N,17.30; C₂₆H₂₈N₆O₃ 0.3H₂O requires; C, 65.34; H, 6.03; N, 17.58%. M.p.234-236° C. 69^(D) (c)

39 ¹Hnmr(DMSOd₆, 400 MHz) δ: 0.64(m, 2H), 0.92(m, 2H), 1.76(m, 1H),2.28(m, 4H), 2.40(m, 1H), 2.62(m, 2H), 2.70(m, 2H), 2.80(m, 1H), 3.50(m,1H), 3.76(s, 3H), 3.83(t, 2H), 4.73(s, 2H), 4.84(m, 1H), 6.13(s, 1H),6.52(s, 1H), 6.74(m, 2H), 7.12(dd, 1H), 11.00(s, 1H). # LRMS: m/z(ES⁺)447[MH⁺]Microanalysis found: C, 68.72; H, 6.76; N, 12.22. C₂₆H₃₀N₄O₃;0.4H₂O requires; C, 68.82; H, 6.84; N, 12.35%. 70^(d) (c)

8 ¹Hnmr(DMSOd₆, 400 MHz) δ: 0.61(m, 2H), 0.88(m, 2H), 1.76(m, 1H),2.24(m, 4H), 2.27(s, 3H), 2.40(m, 1H), 2.62(m, 2H), 2.67(m, 2H), 2.82(m,1H), 3.46(m, 1H), 3.73(s, 3H), 3.79(t, 2H), 4.70(s, 2H), 4.82(m, 1H),6.13(s, 1H), 6.52(s, 1H), 6.71(m, 2H), 7.09(dd, 1H), # 11.00(s, 1H).LRMS: m/z(ES⁺) 447[MH⁺]Microanalysis found: C, 68.40; H, 6.85; N, 12.19.C₂₆H₃₀N₄O₃; 0.5H₂O requires; C, 68.55; H, 6.86; N, 12.30%. 71^(D) (a)

84 ¹Hnmr(DMSOd₆, 400 MHz) δ: 0.65(m, 2H), 0.93(m, 2H), 1.60(m, 1H),1.68(m, 2H), 1.95(m, 1H), 2.20(m, 1H), 2.38(s, 3H), 2.60(m, 1H), 2.73(m,2H), 2.96(m, 1H), 3.49(m, 1H), 3.76(s, 3H), 3.83(m, 3H), 3.94(m, 1H),4.75(s, 2H), 6.14(s, 1H), 6.52(s, 1H), 6.78(m, 2H), # 7.14(dd, 1H),11.00(s, 1H). LRMS: m/z(ES⁺) 461[MH⁺]. Microanalysis found: C, 70.30; H,7.04; N, 12.09. C₂₇H₃₂N₄O₃ requires; C, 70.41; H, 7.00; N, 12.16%.72^(D) (a)

73 ¹Hnmr(DMSOd₆, 400 MHz) δ: 0.63(m, 2H), 0.92(m, 2H), 1.60(m, 1H),1.67(m, 2H), 1.95(m, 1H), 2.20(m, 1H), 2.37(s, 3H), 2.60(m, 1H), 2.72(t,2H), 2.95(m, 1H), 3.49(m, 1H), 3.75(s, 3H), 3.82(m, 3H), 3.94(m, 1H),4.73(s, 2H), 6.12(s, 1H), 6.51(s, 1H), 6.78(m, 2H), # 7.12(dd, 1H),10.97(s, 1H). LRMS: m/z(ES⁻) 459[M − H⁻]. Microanalysis found: C, 69.80;H, 7.07; N, 12.01. C₂₇H₃₂N₄O₃; 0.25H₂O requires; C, 69.73; H, 7.04; N,12.05%. 73^(D,3) (b)

87 ¹Hnmr(DMSOd₆, 400 MHz) δ: 0.64(m, 2H), 0.95(m, 2H), 2.40(s, 3H),2.92(t, 2H), 3.50(m, 1H), 3.78(s, 3H), 3.95(t, 2H), 4.78(s, 2H), 6.17(s,1H), 6.56(s, 1H), 7.07(d, 1H), 7.50(d, 1H), 11.12(s, 1H). LRMS: m/z(ES⁺)363[MH⁺]. # Microanalysis found: C, 66.98; H, 6.07; N, 14.70.C₂₁H₂₂N₄O₂; 0.70H₂O requires; C, 67.25; H, 6.29; N, 14.94%. 74 (b)

95 ¹Hnmr(CDCl₃, 400 MHz) δ: 0.71(m, 2H), 0.97(m, 2H), 1.80-2.00(m, 4H),2.07(m, 2H), 2.33(s, 3H), 3.00(m, 1H), 3.10(t, 2H), 3.39(m, 1H), 3.85(s,3H), 4.02(t, 2H), 4.84(s, 2H), 6.29(s, 1H), 6.65(s, 1H), 7.07(d, 1H),7.40(d, 1H), 10.03(m, 1H). # LRMS: m/z(ES⁺) 447[MH⁺]Microanalysis found:C, 67.44; H, 6.96; N, 14.92. C₂₆H₃₁N₅O₂; 0.25CH₂Cl₂ requires; C, 67.54;H, 6.80; N, 15.00%. 75^(D) (b)

35 ¹Hnmr(DMSOd₆, 400 MHz) δ: 0.65(m, 2H), 0.95(m, 2H), 2.61(t, 2H),2.94(t, 2H), 3.50(m, 3H), 3.75(s, 2H), 3.78(s, 3H), 3.95(t, 2H), 4.48(m,1H), 4.78(s, 2H), 6.15(s, 1H), 6.53(s, 1H), 7.25(d, 1H), 7.57(d, 1H).Microanalysis found: C, 64.10; H, 6.49; N, 16.10. # C₂₃H₂₇N₅O₃; 0.5H₂Orequires; C, 65.54; H, 6.46; N, 16.62%. 76^(D) (b)

16 ¹Hnmr(CDCl₃, 400 MHz) δ; 0.75(m, 2H), 0.99(m, 2H), 2.37(bs, 3H),2.68(m, 2H), 3.14(t, 2H), 3.36(s, 3H), 3.39(m, 1H), 3.57(m, 2H), 3.73(m,2H), 3.84(s, 3H), 4.03(t, 2H), 4.88(s, 2H), 6.30(s, 1H), 6.68(s, 1H),7.38(m, 1H), 7.45(d, 1H), 10.37(bs, 1H). # LRMS: m/z(ES⁺) 472[MNa⁺].Microanalysis found: C, 65.82; H, 7.06; N, 15.01. C₂₅H₃₁N₅O₃; 0.3H₂Orequires; C, 66.00; H, 7.00; N, 15.39%. 77^(D) (b)

30 ¹Hnmr(CDCl₃, 400 MHz) δ: 0.75(m, 2H), 1.00(m, 2H), 3.05(m, 2H),3.28(s, 3H), 3.40(m, 1H), 3.64(m, 1H), 3.83(s, 3H), 3.97(m, 2H), 4.14(m,2H), 4.24(m, 2H), 4.83(s, 2H), 6.33(d, 1H), 6.65(s, 1H), 7.06(d, 1H),8.38(d, 1H). LRMS: m/z(ES⁺) 448.8[MH⁺]. # Microanalysis found: C, 65.15;H, 6.56; N, 14.92. C₂₅H₂₉N₅O₃; 0.75H₂O requires; C, 65.13; H, 6.67; N,15.19%. 78^(D) (b)

26 ¹Hnmr(CDCl₃, 400 MHz) δ: 0.78(m, 2H), 1.01(m, 2H), 2.22(m, 2H),3.18(m, 2H), 3.37(s, 3H), 3.40(m, 2H), 3.84(s, 3H), 4.02(m, 3H), 4.21(m,1H), 4.90(s, 2H), 6.32(s, 1H), 6.65(s, 1H), 7.10(d, 1H), 8.38(d, 1H).LRMS: m/z(ES⁺) 462.9[MH⁺]. # Microanalysis found: C, 63.38; H, 6.60; N.14.15. C₂₆H₃₁N₅O₃; 0.45CH₂Cl₂ requires C, 63.56; H, 6.94; N, 14.01%. 79(a)

51 ¹Hnmr(DMSOd₆, 400 MHz) δ: 0.55(m, 2H), 0.93(m, 2H), 1.55(m, 1H),1.75(m, 1H), 2.72(m, 1H), 3.00(m, 1H), 3.28-3.38(m, 4H), 3.50(m, 2H),3.76(m, 5H), 3.90(m, 2H), 4.28(s, 1H), 4.80(s, 2H), 6.18(d, 1H), 6.56(d,1H), 7.13(d, 1H), 8.24(d, 1H), 11.09(s, 1H). # LRMS: m/z(ES⁺)460[MH⁺]Microanalysis found: C, 67.26; H, 6.42; N, 15.02. C₂₆H₂₉N₅O₃;0.25H₂O requires; C, 67.96; H, 6.36; N, 15.24%. 80 (a)

¹Hnmr(CDCl₃, 400 MHz) δ: 0.68(m, 2H), 0.95(m, 2H), 1.03(d, 3H), 2.32(s,3H), 2.98(m, 1H), 3.02(t, 2H), 3.26(m, 5H), 3.50(m, 1H), 3.80(s, 3H),3.82(s, 2H), 2.99(t, 2H), 4.83(s, 2H), 6.27(d, 1H), 6.62(d, 1H), 8.48(s,1H). LRMS: m/z(ES⁺) 487[MNa⁺] 81 (a)

¹Hnmr(DMSOd₆ + TFAd, 400 MHz) δ: 0.78(m, 2H), 1.02(m, 2H), 1.18(m, 4H),3.07(m, 4H), 3.17(t, 2H), 3.22(s, 3H), 3.30(m, 1H), 3.54(m, 1H), 3.82(s,3H), 4.12(t, 2H), 4.60(m, 2H), 5.03(s, 2H), 6.44(s, 1H), 7.08(s, 1H),8.76(s, 1H). LRMS: m/z(ES⁺) 477[MH⁺] 82 (b)

32 ¹Hnmr(CDCl₃, 400 MHz) δ: 0.20(m, 2H), 0.57(m, 2H), 0.72(m, 2H),1.00(m, 2H), 2.60(d, 2H), 3.32(m, 1H), 3.85(s, 3H), 4.03(t, 2H), 4.13(t,2H), 4.91(s, 2H), 6.37(d, 1H), 6.65(s, 1H), 6.77(s, 1H). LRMS: m/z(ES⁺)392[MH⁺] 83^(D) (a)

80 ¹Hnmr(DMSOd₆, 400 MHz) δ: 0.65(m, 2H), 0.93(m, 2H), 2.95(m, 4H),3.49(m, 1H), 3.69(m, 4H), 3.77(s, 3H), 3.90(t, 2H), 3.92(t, 2H), 4.76(s,2H), 6.17(d, 1H), 6.50(s, 1H), 6.54(d, 1H), 11.12(s, 1H). # LRMS:m/z(ES⁺) 445[MNa⁺]Microanalysis found: C, 62.44; H, 6.21; N, 19.60.C₂₂H₂₆N₆O₃ requires; C, 62.54; H, 6.20; N, 19.89%. 84^(D) (a)

66 ¹H-NMR(DMSOd₆, 400 MHz) δ: 0.66(m, 2H), 0.93(m, 2H), 1.59(d, 1H),1.80(d, 1H), 2.45(d, 1H), 2.76(d, 1H), 2.94(t, 2H), 3.47(s, 1H), 3.52(d,2H), 3.77(m, 5H), 3.01(d, 1H), 3.95(t, 2H), 4.33(s, 1H), 4.78(s, 2H),6.14(d, 1H), 6.53(d, 1H), 7.29(d, 1H), 7.56(d, 1H), 11.09(s, 1H). #LRMS: m/z(ES⁺) 482[MNa⁺]Microanalysis: Found: C, 67.67; H, 6.38; N,15.12; C₂₆H₂₉N₅O₃ requires; C, 67.96; H, 6.36; N, 15.24% 85^(D) (c)

70 ¹H-NMR(DMSOd₆, 400 MHz) δ: 1.30(m, 5H), 1.79(m, 5H), 2.38(m, 4H),2.94(t, 2H), 3.52(s, 2H), 3.57(m, 4H), 3.79(s, 3H), 3.93(t, 2H), 4.14(t,1H), 4.77(s, 2H), 6.57(m, 2H), 7.27(d, 1H), 7.57(d, 1H), 11.03(s, 1H). #LRMS: m/z(APCl⁺) 490[MH⁺]. Microanalysis: Found: C, 68.84; H, 7.33; N,14.18; C₂₈H₃₅N₅O₃ requires; C, 68.69; H, 7.21; N, 14.30% M.p. 233-235°C. 86^(D) (a)

76 ¹H NMR(DMSOd₆, 400 MHz) δ: 1.16(d, 6H), 2.72(t, 2H), 3.28(s, 3H),3.39(m, 2H), 3.44(m, 2H), 3.80(s, 3H), 3.87(t, 2H), 4.54(m, 3H), 6.19(s,1H), 6.38(d, 1H), 6.58(2xs, 2H), 7.15(d, 1H), 10.84(s, 1H) LRMS:m/z(ES⁺) 424[MH⁺] # Microanalysis: Found: C, 65.18; H, 7.00; N, 16.41;C₂₃H₂₉N₅O₃ requires; C, 65.23; H, 6.90; N, 16.54% M.p. 160-162° C.

EXAMPLE 875-Isopropyl-7-methoxy-2-(5-morpholin-4-ylmethyl-3,4-dihydro-1H-[2,6]naphthyridin-2-yl)-3H-quinazolin-4-onedihydrochloride

[1251]

[1252] The chloro compound from preparation 269 (76 mg, 0.3 mmol) wasmixed with the naphthyridine from preparation 117 (93 mg, 0.4 mmol) andN,N-diisopropylethylamine (129 μl, 1 mmol) in n-butanol (5 ml) and themixture was heated under reflux for 2 hours. The reaction mixture wascooled to room temperature and ethyl acetate added. The solution waswashed with water and brine then dried over magnesium sulphate. Theresidue was purified by chromatography on silica gel using methanol indichloromethane as eluant (gradient from 0:100 to 7:93). The materialobtained was dissolved in dichloromethane and ethereal hydrogen chloride(1M, 2 ml) was added. The solvent was evaporated under reduced pressureto give the title compound as on off white solid (73 mg).

[1253]¹H-NMR (DMSOd₆, 400 MHz) δ: 1.14 (d, 6H), 2.96 (t, 2H), 3.35 (m,4H), 3.82 (s, 3H), 3.91 (m, 4H), 4.00 (t, 2H), 4.51 (m, 1H), 4.55 (s,2H), 4.95 (s, 2H), 6.68 (s, 1H), 6.91 (s, 1H), 7.33 (d, 1H), 8.47 (d,1H)

[1254] LRMS: m/z (ES⁺) 450 [MH⁺]

[1255] Microanalysis: Found: C, 57.77; H, 6.65; N, 13.25. C₂₅H₃₁N₅O₃2HCl requires; C, 57.47; H, 6.37; N, 13.40%

EXAMPLES 88 to 122

[1256] The compounds of the following tabulated examples, (where nrepresents 1, 2 or 3 depending on the nature of R1), of the generalformula:

[1257] were prepared by the general method outlined below using theappropriate chloro compound and the cyclic amine.

[1258] General Procedure for Hydrochloride Salts.

[1259] To a solution of the chloro-quinazolinone (1 eq) in n-butanol (15ml per mmol) under nitrogen was added N,N-diisopropylethylamine ortriethylamine (1.7-8 eq) and the appropriate secondary amine (1-2 eq).The resultant mixture was then heated under reflux for 1-6 hours, cooledand the product was isolated by filtration, washing with n-butanol anddiethyl ether (method a)

[1260] Some reaction mixtures were concentrated under reduced pressure,the residue partitioned between dichloromethane and water, the organicphase separated, dried (MgSO₄) and evaporated under reduced pressure,(method b).

[1261] Some products were additionally purified by column chromatographyon silica gel using dichloromethane: methanol or dichloromethane:methanol: 0.88 ammonia as eluants, (method c).

[1262] The products that were obtained were dissolved in dichloromethaneand ethereal hydrogen chloride solution was added. The solvents wereevaporated under reduced pressure to give the product as thehydrochloride salt.

[1263] In the table following: Ex No. Yield (method) R1 R2 %Spectroscopic and analytical data  88 (c)

(I) 55 ¹H-NMR (DMSOd₆, 400 MHz) δ: 1.17 (d, 6H), 2.87 (s, 3H), 2.96 (t,2H), 3.26 (s, 3H), 3.40 (t, 2H), 3.73 (t, 2H), 3.82 (s, 3H), 4.09 (t,2H), 4.42 (m, 1H), 4.54 (s, 2H), 5.07 (s, 2H), 6.78 (s, 1H), 7.29 (d,1H), 7.41 (s, 1H), 8.43 # (d, 1H). LRMS: m/z (ES⁺) 452[MH⁺]Microanalysis: Found: C, 55.84; H, 6.85; N, 12.82. C₂₅H₃₃N₅O₃ 2HCl0.75 H₂O requires; C, 55.81; H, 6.84; N, 13.02%  89 (c)

(I) 41 ¹H-NMR (DMSOd₆, 400 MHz) δ: 1.25 (d, 6H), 1.88 (s, 4H), 2.85 (s,4H), 3.14 (t, 2H), 3.88 (s, 3H), 4.06 (m, 4H), 4.57 (m, 1H), 4.91 (s,2H), 6.72 (d, 1H), 6.76 (d, 1H), 6.55 (s, 1H). LRMS: m/z (ES⁺) # 435[MH⁺]  90^(D)(a)

(I) 91 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.16 (d, 6H), 2.66 (t, 2H), 3.80 (s,3H), 3.98 (t, 2H), 4.50 (m, 1H), 4.88 (s, 2H), 6.70 (s, 1H), 6.77 (d,1H), 6.88 (s, 1H), 7.83 (d, 1H), 7.93 (s, 2H). LRMS: m/z (ES⁺) # 444[MH⁺]  91 (a)

(I) 77 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.18 (d, 6H), 2.82 (m, 2H), 3.27 (s,3H), 3.46 (m, 2H), 3.51 (m, 2H), 3.80 (s, 3H), 4.00 (t, 2H), 4.48 (m,1H), 4.60 (s, 2H), 6.79 (s, 1H), 7.30 (s, 1H), 7.68 (s, 2H), 8.45 (s,1H). LRMS: m/z # (ES⁺) 440 [MH⁺]. Microanalysis: Found: C, 51.50; H,6.13; N, 18.97; C₂₂H₂₉N₇O₃ 2 HCl requires: C, 51.57; H, 6.10; N, 19.13% 92 (a)

(I) 78 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.19 (d, 6H), 3.00 (s, 3H), 3.13 (m,2H), 3.82 (s, 3H), 4.07 (m, 2H), 4.42 (m, 1H), 4.83 (s, 2H), 6.80 (d,1H), 6.98 (d, 1H), 7.37 (s, 1H), 7.69 (d, 1H). LRMS: m/z (ES⁺) 480 #[MH⁺]  93 (a)

(I) 73 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.19 (m, 9H), 3.00 (m, 2H), 3.28 (s,3H), 3.70 (q, 2H), 3.84 (s, 3H), 3.94 (m, 2H), 4.48 (m, 1H), 4.95 (s,2H), 6.75 (s, 1H), 7.08 (s, 1H), 8.60 (s, 1H). LRMS: m/z (ES⁺) 409 #[MH⁺]. Microanalysis: Found: C, 54.90; H, 6.49; N, 17.41 C₂₂H₂₈N₆O₂ 2HClrequires; C, 54.89; H, 6.28; N, 17.46%  94 (a)

(I) 35 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.17 (d, 6H), 3.03 (m, 2H), 3.25 (s,2H), 3.40 (s, 2H), 3.82 (m, 4H), 3.97 (m, 4H), 4.26 (m, 3H), 4.43 (s,1H), 4.52 (m, 1H), 4.90 (s, 2H), 6.90 (s, 1H), 7.30 (m, 3H). LRMS: m/z(ES⁺) # 449 [MH⁺]. Microanalysis: Found: C, 58.97; H, 6.63; N, 10.60C₂₆H₃₂N₄O₃2HCl 0.4 H₂O requires; C, 59.07; H, 6.63; N, 10.60%  95 (c)

(I) 61 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.17 (d, 6H), 2.82 (m, 2H), 3.82 (s,3H), 4.13 (m, 2H), 4.44 (m, 1H), 5.00 (s, 4H), 6.75 (d, 1H), 6.79 (s,1H), 7.32 (s, 1H), 7.54 (m, 1H), 7.68 (d, 1H), 7.78 (d, 1H), 8.07 (m,1H), 8.63 (d, 1H). LRMS: # m/z (ES⁺) 457 [MH⁺]. Microanalysis: Found: C,54.01; H, 5.75; N, 14.06; C₂₆H₂₈N₆O₂3HCl 0.6 H₂O requires; C, 54.15; H,5.63; N, 14.57%  96 (c)

(I) 56 ¹H-NMR (CDCl₃, 400 MHz) δ: 1.23 (d, 6H), 2.82 (t, 2H), 3.06 (t,2H), 3.34 (s, 3H), 3.50 (t, 2H), 3.80 (s, 3H), 3.86 (m, 4H), 4.76 (m,1H), 4.80 (s, 2H), 6.70 (s, 2H), 7.10 (m, 1H), 7.20 (m, 2H). LRMS: m/z(ES⁺) 437 # [MH⁺]. Microanalysis: Found: C, 55.36; H, 6.78; N, 10.14.C₂₅H₃₂N₄O₃ 2HCl 0.5 CH₂Cl₂ requires; C, 55.49; H, 6.39; N, 10.15%  97(c)

(I) 65 ¹H-NMR (DMSOd₆, 400 MHz) δ: 1.16 (d, 6H), 2.82 (s, 6H), 2.89 (m,2H), 3.38 (t, 2H), 3.84 (s, 3H), 4.04 (m, 2H), 4.09 (m, 2H), 4.43 (m,1H), 4.90 (s, 1H), 5.02 (s, 2H), 6.78 (m, 2H), 7.30 (s, 1H), 7.80 (d,1H), 8.41 (s, 1H), 10.80 # (s, 1H). LRMS: m/z (ES⁺) 437 [MH⁺].Microanalysis: Found: C, 52.19; H, 6.79; N, 14.92; C₂₄H₃₂N₆O₃ 3HCl 0.5H₂O requires; C, 51.94; H, 6.54; N, 15.14%  98 (c)

(I) 40 ¹H-NMR (CDCl₃, 400 MHz) δ: 1.24 (d, 6H), 2.20 (s, 6H), 3.09 (t,2H), 3.38 (s, 2H), 3.85 (m, 5H), 4.56 (m, 1H), 4.80 (s, 2H), 6.70 (s,2H), 7.15 (m, 3H). LRMS: m/z (ES⁺) 407 [MH⁺]  99 (a)

A 66 ¹H-NMR (DMSOd₆, 400 MHz) δ: 1.17 (d, 6H), 2.53 (m, 2H), 3.17 (s,6H), 3.81 (s, 3H), 4.00 (m, 2H), 4.48 (m, 1H), 4.85 (s, 2H), 6.78 (s,1H), 7.12 (s, 1H). LRMS: m/z (ES⁺) 410 [MH⁺]. Microanalysis: Found: # C,50.81; H, 6.16; N, 19.44; C₂₁H₂₇N₇O₂2HCl 0.75 H₂O requires; C, 50.86; H,6.20; N, 19.77% 100 (a)

(I) 99 ¹H-NMR (DMSOd₆, 400 MHz) δ: 1.16 (d, 6H), 3.16 (s, 6H), 3.24 (s,3H), 3.50 (t, 2H), 3.59 (t, 3H), 3.80 (s, 3H), 3.90 (m, 2H), 4.50 (m,1H), 4.73 (s, 2H), 6.72 (s, 1H), 6.80 (s, 1H), 8.38 (t, 1H). LRMS: m/z(ES⁺) # 468 [MH⁺]. Microanalysis: Found: C, 53.27; H, 6.66; N, 17.99C₂₄H₃₃N₇O₃2HCl requires; C, 53.33; H, 6.53; N, 18.14%  101^(D)(a)

(I) 55 ¹H-nmr (CD₃OD, 400 MHz) δ: 1.23 (d, 6H), 2.04 (m, 2H), 2.13 (m,2H), 3.03 (m, 2H), 3.39 (m, 5H), 3.50 (m, 2H), 3.62 (m, 1H), 3.93 (s,3H), 4.07 (m, 2H), 4.49 (m, 1H), 4.55 (s, 2H), 4.98 (s, 2H), 6.91 (s,1H), 6.99 (s, # 1H), 7.35 (d, 1H), 8.53 (d, 1H). LRMS: m/z (ES⁺) 478[MH⁺]. Microanalysis found: C, 58.97; H, 6.92; N, 12.71; C₂₇H₃₅N₅O₃ 2HCl requires C, 58.91; H, 6.77; N, 12.72% 102 (c)

(I) 45 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.18 (d, 6H), 1.26 (m, 2H), 2.91 (m,2H), 3.25 (s, 3H), 3.82 (s, 3H), 4.08 (m, 4H), 4.32 (m, 1H), 4.41 (m,1H), 4.64 (s, 2H), 5.04 (s, 2H), 6.78 (s, 1H), 7.23 (d, 1H), 7.10 (s,1H), 8.38 (d, 1H), # 10.78 (s, 1H). LRMS: m/z (ES⁺) 450 [MH⁺].Microanalysis found: C, 55.62; H, 6.41; 12.78; C₂₅H₃₁N₅O₃2HCl H₂Orequires; C, 55.56; H, 6.53; 12.96% 103 (b)

(I) 63 ¹H-NMR (CDCl₃, 400 MHz) δ: 1.25 (d, 6H), 2.59 (m, 4H), 3.14 (t,2H), 3.76 (m, 6H), 3.88 (s, 3H), 4.00 (t, 2H), 4.54 (m, 1H), 4.89 (s,2H), 6.71 (d, 1H), 6.76 (d, 1H), 8.57 (s, 1H), 9.75 (s, 1H). LRMS: m/z(ES⁺) 473 # [MH⁺]Microanalysis: Found: C, 54.49; H, 6.41; N, 15.58.C₂₄H₃₀N₆O₃ 2 HCl 0.25 H₂O requires; C, 54.60; H, 6.20; N, 15.92% 104 (c)

(I) 40 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.18 (d, 6H), 2.87 (s, 6H), 2.95 (t,2H), 3.83 (s, 3H), 4.08 (t, 2H), 4.46 (m, 1H), 4.52 (s, 2H), 5.04 (s,2H), 6.72 (s, 1H), 7.31 (m, 2H), 8.46 (d, 1H). LRMS: m/z (ES⁺) 408 #[MH⁺]Microanalysis: Found: C, 54.47; H, 6.62; N, 13.65. C₂₃H₂₉N₅O₂2HCl1.5 H₂O requires C, 54.44; H, 6.75; N, 13.80% 105 (c)

(I) 61 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.08 (d, 6H), 2.80 (s, 6H), 3.18 (s,2H), 3.33 (t, 2H), 3.82 (s, 3H), 3.95 (m, 2H), 4.09 (m, 2H), 4.42 (m,1H), 4.07 (s, 2H), 6.80 (s, 1H), 7.04 (d, 1H), 7.42 (s, 1H), 7.70 (d,1H). LRMS: m/z # (ES⁺) 437 [MH⁺]Microanalysis: Found: C, 51.75; H, 6.72;N, 14.93. C₂₄H₃₂N₆O₃ 3HCl 0.6 H₂O requires C, 51.78; H, 6.53; N, 15.09%106 (c)

(I) 88 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.20 (d, 6H), 2.60 (s, 3H), 2.96 (t,2H), 3.86 (s, 3H), 4.08 (t, 2H), 4.42 (m, 1H), 5.05 (s, 2H), 5.42 (s,2H), 6.80 (s, 1H), 6.84 (d, 1H), 7.26 (m, 2H), 7.41 (s, 1H), 7.58 (s,2H). LRMS: m/z # (ES⁺) 444 [MH⁺]. Microanalysis: Found: C, 59.19; H,6.47; N, 13.28; C₂₆H₂₉N₅O₂ 2HCl 0.6 H₂O requires; C, 59.23; H, 6.16;13.28% 107 (c)

(II) 67 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.64 (m, 4H), 2.48 (s, 2H), 2.90 (s,3H), 3.07 (t, 3H), 3.26 (s, 3H), 3.42 (t, 2H), 3.70 (t, 2H), 3.80 (s,3H), 3.93 (m, 2H), 4.05 (t, 2H), 4.32 (m, 1H), 4.58 (s, 2H), 4.92 (s,2H), 6.86 (s, 1H), 6.93 # (s, 1H) 8.74 (s, 1H), 10.17 (s, 1H). LRMS: m/z(ES⁺) 495 [MH⁺]. Microanalysis found: C, 55.21; H, 6.59; N, 14.71;C₂₆H₃₄N₆O₄2HCl requires; C, 55.03; H, 6.39; N, 14.81% 108 (a)

(II) 57 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.64 (m, 4H), 1.98 (m, 4H), 3.12 (m,4H), 3.42 (m, 2H), 3.61 (s, 2H), 3.81 (s, 3H), 3.97 (m, 2H), 4.18 (s,2H), 4.22 (m, 1H), 4.62 (m, 2H), 5.08 (s, 2H), 6.78 (s, 1H), 7.39 (s,1H), 8.76 (s, 1H), 10.73 # (s, 1H) LRMS: m/z (ES⁺) 477 [MH⁺] 109 (c)

(II) 71 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.62 (m, 4H), 2.86 (s, 6H), 3.09 (t,3H), 3.42 (m, 2H), 3.81 (s, 3H), 3.93 (m, 2H), 4.11 (m, 2H), 4.27 (m,1H), 4.57 (s, 2H), 5.06 (s, 2H), 6.77 (s, 1H), 8.76 (s, 1H), 10.37 (s,1H). LRMS: m/z # (ES⁻) 449 [MH⁻]Microanalysis found: C, 56.66; H, 6.47;N, 16.33; C₂₄H₃₀N₆O₃ 1.6 HCl requires; C, 56.65; H, 6.26; N, 16.51% 110(c)

(II) 60 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.64 (m, 4H), 1.98 (m, 4H), 2.95 (m,2H), 3.40 (m, 6H), 3.80 (s, 3H), 3.99 (m, 4H), 4.32 (m, 1H), 4.59 (s,2H), 4.95 (s, 2H), 6.63 (s, 1H), 7.30 (d, 1H), 8.42 (d, 1H), 10.27 (s,1H). LRMS: m/z # (ES⁺) 467 [MH⁺] 111 (a)

(II) 75 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.66 (m, 4H), 2.46 (s, 2H), 3.42 (t,2H), 3.81 (s, 3H), 3.93 (d, 2H), 4.23 (m, 3H), 4.43 (s, 2H), 5.08 (s,2H), 6.74 (s, 1H), 7.22 (s, 1H), 7.61 (s, 1H), 9.15 (s, 1H). LRMS: m/z(ES⁺) 482 # [MH⁺]. Microanalysis found: C, 54.95; H, 5.86; N, 15.77;C₂₀H₂₃N₅O₃ HCl H₂O requires; C, 55.11; H, 6.01; N, 16.07% 112 (c)

(II) 18 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.66 (m, 4H), 3.03 (m, 2H), 3.35 (s,4H), 3.43 (m, 2H), 3.84 (s, 3H), 3.90 (s, 6H), 4.13 (s, 2H), 4.24 (m,1H), 4.57 (s, 2H), 5.13 (s, 2H), 6.78 (s, 1H), 7.32 (d, 1H), 7.58 (s,1H), 8.47 (d, 1H), 11.0 # (s, 1H). LRMS: m/z (ES⁺) 492 [MH⁺] 113 (c)

(II) 10 ¹H-nmr (CD₃OD, 400 MHz) δ: 1.67 (m, 4H), 2.87 (s, 6H), 3.15 (s,2H), 3.43 (m, 2H), 3.81 (s, 3H), 3.95 (m, 2H), 4.00 (s, 2H), 4.32 (m,1H), 4.54 (s, 2H), 4.98 (s, 2H), 6.69 (s, 1H), 7.30 (d, 1H), 8.46 (d,1H). LRMS: m/z # (ES⁺) 450 [MH⁺] 114 (c)

(II) 77 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.63 (m, 4H), 3.15 (s, 4H), 3.22 (t,2H), 3.42 (m, 3H), 3.88 (m, 11H), 4.28 (m, 1H), 4.38 (s, 2H), 4.92 (s,2H), 6.73 (s, 1H), 7.27 (s, 1H), 7.33 (d, 1H), 7.61 (d, 1H), 11.17 (s,1H). LRMS: m/z # (ES⁺) 491 [MH⁺]; Microanalysis found: C, 58.45; H,6.54; N, 9.58; C₂₈H₃₄N₄O₄ 2HCl 0.65 H₂O requires; C, 58.46; H, 6.54; N,9.74% 115 (a)

(II) 70 ¹H NMR (DMSOd₆, 400 MHz) δ: 1.67 (m, 4H), 3.12 (s, 2H), 3.22 (s,3H), 3.42 (m, 2H), 3.82 (s, 3H), 3.94 (m, 12H), 5.01 (s, 2H), 6.79 (s,1H), 7.32 (m, 2H), 7.51 (m, 2H), 11.47 (s, 1H). LRMS: m/z (ES⁺) 491 #[MH⁺]. Microanalysis found: C, 58.76; H, 6.53; N, 9.65; C₂₈H₃₄N₄O₄ 2HCl0.5 H₂O requires; C, 58.74; H, 6,51; N, 9.79% 116 (c)

(III) 83 ¹H-NMR (DMSOd₆, 400 MHz) δ: 1.47 (m, 1H), 1.90 (m, 6H), 2.52(m, 2H), 3.35 (m, 6H), 3.90 (m, 11H), 4.80 (s, 2H), 5.80 (t, 1H), 6.98(s, 1H), 7.00 (d, 1H), 7.19 (s, 1H), 7.71 (d, 1H). LRMS: m/z (ES⁺) 491 #[MH⁺]. Microanalysis: Found: C, 53.69; H, 6.54; N, 13.89; C₂₇H₃₄N₆O₃3HCl 0.25 H₂O requires; C, 53.65; H, 6.25; N, 13.90% 117 (a)

(III) 54 ¹H-NMR (DMSOd₆, 400 MHz) δ: 1.49 (m, 1H), 1.82 (m, 2H), 2.50(m, 2H), 3.08 (m, 2H), 3.28 (s, 3H), 3.53 (t, 2H), 3.61 (m, 2H), 3.80(m, 4H), 4.02 (m, 3H), 4.78 (s, 2H), 5.80 (t, 1H), 6.94 (d, 1H), 7.02(d, 1H), 7.12 (s, 1H), # 7.72 (d, 1H). LRMS: m/z (ES⁺) 452 [MH⁺].Microanalysis: Found: C, 53.37; H, 5.97; N, 12.66; C₂₄H₂₉N₅O₄2HCl 0.25CH₂Cl₂ requires; C, 53.38; H, 5.82, 12.83% 118 (c)

(III) 87 ¹H-NMR (DMSOd₆, 400 MHz) δ: 1.50 (m, 1H), 1.82 (m, 2H), 2.51(m, 2H), 2.81 (s, 6H), 3.11 (m, 2H), 3.32 (t, 2H), 3.82 (m, 4H), 3.91(m, 2H), 4.01 (m, 3H), 4.80 (s, 2H), 5.80 (t, 1H), 6.95 (s, 1H), 6.99(d, 1H), 7.13 (s, 1H), # 7.69 (d, 1H). LRMS: m/z (ES⁺) 465 [MH⁺].Microanalysis: Found: C, 52.32; H, 6.45; N, 14.66; C₂₅H₃₂N₆O₃3HClrequires; C, 52.32; H, 6.15; N, 14.64% 119 (a)

(III) 89 ¹H-NMR (DMSOd₆, 400 MHz) δ: 1.49 (m, 1H), 1.80 (m, 2H), 2.50(m, 2H), 3.80 (m, 5H), 4.06 (m, 3H), 4.98 (s, 2H), 5.79 (m, 1H), 6.73(d, 1H), 7.95 (d, 1H), 7.22 (s, 1H), 7.86 (d, 1H), 8.08 (s, 2H). LRMS:m/z (ES⁺) # 394 [MH⁺]. Microanalysis: Found: C, 50.46; H, 5.22; N,13.68; C₂₁H₂₃N₅O₃3HCl requires; C, 50.16; H, 5.21; N, 13.93% 120 (a)

—Cl 17 ¹H-NMR (DMSOd₆, 400 MHz) δ: 1.64 (s, 4H), 2.51 (s, 4H), 2.93 (m,2H), 3.73 (s, 2H), 3.81 (s, 3H), 3.95 (t, 2H), 4.81 (s, 2H), 6.70 (s,1H), 6.73 (s, 1H), 8.58 (s, 1H). LRMS: m/z (ES⁺) 427, 427 [MH⁺]M.p. #190-191° C. 121 (a)

—Cl 45 ¹H-NMR (DMSOd₆, 400 MHz) δ: 2.02 (d, 1H), 2.40 (d, 1H), 2.90 (s,2H), 3.42 (m, 1H), 3.74 (d, 1H), 3.82 (s, 3H), 4.02 (m, 2H), 4.28 (d,1H), 4.48 (s, 1H), 4.65 (m, 4H), 4.97 (s, 2H), 6.81 (s, 1H), 7.00 (s,1H), 7.30 (d, 1H), # 8.42 (d, 1H). LRMS: m/z (ES⁺) 454, 456 [MH⁺]. M.p.314-315° C. 122 (c)

(IV) ¹H-nmr (CDCl₃ + TFAd, 400 MHz) δ: 0.77 (m, 2H), 1.14 (m, 2H), 1.44(t, 3H), 2.96 (m, 1H), 3.36 (t, 2H), 3.39 (s, 3H), 3.54 (q, 2H), 3.60(m, 2H), 3.80 (m, 2H), 3.88 (s, 3H), 4.18 (m, 2H), 4.66 (m, 1H), 4.80(m, 1H), 5.16 (s, # 2H), 6.62 (s, 1H), 6.99 (s, 1H), 8.70 (s, 1H). LRMS:m/z (ES⁺) 487 [MNa⁺]. Microanalysis found: C, 59.08; H, 6.85; N, 16.08.C₂₅H₃₂N₆O₃; HCl; 0.5 H₂O requires C, 58.87; H, 6.72; N, 16.48%.^(D)Triethylamine was used as the base

EXAMPLE 1232-(2-Aminomethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-5-isopropyl-7-methoxy-3H-quinazolin-4-onedihydrochloride

[1264]

[1265] Hydrogen chloride gas was bubbled for 10 minutes into a solutionof the protected amine from preparation 293 (155 mg, 0.32 mmol) indichloromethane at 0° C. The solution was stirred at 0° C. for 1.5 hoursand then the mixture was degassed by a stream of nitrogen being blownthrough the mixture. The solvent was evaporated under reduced pressureand the residue was dried under vacuum to give the title compound as awhite solid (146 mg).

[1266]¹H-nmr (CD₃OD, 400 MHz) δ: 1.23 (d, 6H), 3.21 (t, 2H), 3.90 (s,3H), 4.07 (t, 2H), 4.06 (s, 2H), 4.48 (m, 1H), 4.94 (s, 2H), 6.86 (s,1H), 6.90 (s, 1H), 7.33 (d, 1H), 7.72 (d, 1H)

[1267] LRMS: m/z (ES⁺) 380 [MH⁺]

[1268] Microanalysis: Found: C, 55.61; H, 6.21; N, 15.12; C₂₁H₂₅N₅O₂2HCl requires; C, 55.76; H, 6.02; N, 15.48%

EXAMPLE 1242-(7,8-Dihydro-5H-[1,6]naphthyridin-6-yl)-7-methoxy-5-(1-methyl-piperidin-2-yl)-3H-quinazolin-4-onetrihydrochloride

[1269]

[1270] 3-Methylpentan-3-ol (5 ml) was added to the guanidine frompreparation 286 (86 mg, 0.2 mmol) and potassium t-butoxide (67 mg, 0.6mmol) and the mixture was heated under reflux for 1 hour. A furtherquantity of potassium t-butoxide (45 mg, 0.4 mmol) was added and themixture was heated under reflux for a further 1 hour. The reactionmixture was cooled to room temperature and 1M citric acid (3 ml) wasadded. The mixture was added to water and was basified with 0.5M sodiumhydroxide solution. The solution was extracted with dichloromethane(3×50 ml) and the combined organic solutions were dried over magnesiumsulphate and evaporated under reduced pressure. The residue was purifiedby chromatography on silica gel using methanol and ammonium hydroxide indichloromethane as eluant (gradient from 0:0:100 to 10:1:90). Thematerial isolated was dissolved in dichloromethane and 1M hydrogenchloride in dichloromethane was added. The mixture was evaporated underreduced pressure to give the title compound as a white solid (26 mg).

[1271]¹H-nmr (DMSOd₆ 400 MHz) δ: 1.80 (m, 10H), 2.40 (m, 2H), 3.08 (m,1H), 3.49 (m, 2H), 3.97 (s, 3H), 4.12 (m, 2H), 5.07 (s, 2H), 7.77 (m,1H), 8.00 (d, 1H), 8.60 (m, 1H), 8.63 (d, 1H)

[1272] LRMS: m/z (ES⁺) 406 [MH⁺]

EXAMPLE 1252-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-7-methoxy-5-(1-methyl-piperidin-2-yl)-3H-quinazolin-4-onedihydrochloride

[1273]

[1274] The title compound was obtained from the guanidine frompreparation 287 in 27% yield following the procedure described inExample 124.

[1275]¹H-nmr (DMSOd₆ 400 MHz) δ: 1.80 (m, 10H), 2.85 (t, 2H), 3.80 (m,13H), 4.80 (s, 2H), 6.78 (d, 2H), 6.89 (d, 1H), 7.20 (s, 1H)

[1276] LRMS: m/z (ES⁺) 465 [MH⁺]

EXAMPLE 1267-Methoxy-2-[2-(2-methoxy-ethylamino)-3,4-dihydro-1H-isoquinolin-2-yl]-5-(1-methyl-piperidin-2-yl)-3H-quinazolin-4-onetrihydrochloride

[1277]

[1278] The title compound was obtained from the guanidine frompreparation 288 in 27% yield following a similar procedure to thatdescribed in Example 124.

[1279]¹H-nmr (DMSOd₆ 400 MHz) δ: 1.60 (m, 11H), 3.50 (m, 16H), 4.72 (s,2H), 6.89 (d, 1H), 7.00 (d, 1H), 7.70 (m, 2H)

[1280] LRMS: m/z (ES⁺) 479 [MH⁺]Microanalysis: Found: C, 53.53; H, 6.73;N, 13.66; C₂₆H₃₄N₆O₃ 3HCl 0.25 (CH₃CH₃)₂O requires; C, 53.47; H, 6.56;N, 13.86%

EXAMPLE 1275-(Butane-1-sulfonyl)-7-methoxy-2-[5-(2-methoxy-ethylamino)-3,4-dihydro-1H-[2,6]naphthyridin-2-yl]-3H-quinazolin-4-one

[1281]

[1282] Caesium carbonate (450 mg, 1.38 mmol) was added to the guanidinefrom preparation 224 (177 mg, 0.55 mmol) in N,N-dimethylformamide (2 ml)and the suspension was stirred for 1 hour at room temperature. Theimidazolide solution from preparation 280 (3 ml, 0.46 mmol) was addedand the mixture was stirred at room temperature for 42 hours. Thesolvent was evaporated under reduced pressure and the residue waspartitioned between ethyl acetate (25 ml) and pH7 buffer (40 ml). Thephases were separated and the aqueous solution was extracted with ethylacetate (2×25 ml). The combined organic solutions were washed with brine(3×15 ml), dried over magnesium sulphate and evaporated under reducedpressure.

[1283] The material obtained was dissolved in 1,2-dimethoxyethane (3 ml)and was added to potassium tert-butoxide (139 mg, 1.24 mmol) under anitrogen atmosphere. The mixture was heated under reflux for 1.5 hoursand then was cooled to room temperature and partitioned betweendichloromethane (25 ml) and pH7 buffer. The phases were separated andthe aqueous solution was extracted with dichloromethane (2×25 ml). Thecombined organic solutions were dried over magnesium sulphate andevaporated under reduced pressure. The residue was purified bychromatography on silica gel using methanol in dichloromethane as eluant(gradient from 2:98 to 4:96). The material obtained was dried undervacuum at 60° C. for 24 hours to give the title compound (29 mg).

[1284]¹H-nmr (CDCl₃, 400 MHz) δ: 0.89 (t, 3H), 1.42 (m, 2H), 1.72 (m,2H), 2.63 (m, 2H), 3.38 (s, 3H), 3.59 (t, 2H), 3.68 (m, 2H), 3.79 (m,2H), 3.93 (s, 3H), 3.98 (t, 2H), 4.55 (s, 1H), 4.72 (s, 2H), 6.44 (d,1H), 7.00 (d, 1H), 7.72 (s, 1H), 7.99 (d, 1H)

[1285] LRMS: m/z ES⁺502 [MH⁺]

EXAMPLE 1285-(Butane-1-sulfonyl)-7-methoxy-2-{5-[(Pyridin-2-ylmethyl)-amino]-3,4-dihydro-1H-[2,6]naphthyridin-2-yl}-3H-quinazolin-4-one

[1286]

[1287] The title compound was obtained from the imidazolide solutionfrom preparation 280 and the guanidine from preparation 223 in 7% yieldfollowing the procedure described in Example 127.

[1288]¹H-nmr (CDCl₃, 400 MHz) δ: 0.88 (t, 3H), 1.40 (m, 2H), 1.74 (m,2H), 2.77 (t, 2H), 3.80 (m, 2H), 3.93 (s, 3H), 3.99 (t, 2H), 4.71 (s,2H), 4.77 (d, 2H), 5.70 (m, 1H), 6.47 (d, 1H), 7.00 (m, 1H), 7.16 (m,1H), 7.29 (m, 1H), 7.64 (m, 1H), 7.72 (s, 1H), 8.01 (d, 1H), 8.56 (d,1H)

[1289] LRMS: m/z (ES⁺) 535 [MH⁺]

EXAMPLE 1295-Isopropyl-7-methoxy-2-[1-(2-pyrrolidin-1-yl-ethyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3H-quinazolin-4-one

[1290]

[1291] and

EXAMPLE 1305-Isopropyl-7-methoxy-2-[2-(2-pyrrolidin-1-yl-ethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3H-quinazolin-4-one

[1292]

[1293] The chloro compound from preparation 269 (91 mg, 0.36 mmol) wasadded to a mixture of the amines from preparation 229-A and preparation229-B (60:40 mixture, 206 mg, 0.45 mmol) in n-butanol (3 ml) containingN,N-diisopropylethylamine (350 μl, 2 mmol). The reaction mixture washeated under reflux for 2 hours and then was cooled to room temperatureand diluted with ethyl acetate (350 ml). The organic mixture was washedwith sodium hydrogen carbonate solution (2×15 ml), dried over magnesiumsulphate and evaporated under reduced pressure.

[1294] The residue was purified by chromatography on a Chiralpak® AS 250mm×20 mm column, using diethylamine and propan-2ol in n-hexane(0.05:9.95:90) as eluant at a flow rate of 10 ml/minute to give thetitle compound of Example 129 (31 mg).

[1295]¹H-nmr (CD₃OD, 400 MHz) δ: 1.20 (d, 6H), 1.72 (m, 4H), 2.52 (m,4H), 2.90 (m, 4H), 3.84 (s, 3H), 3.99 (m, 2H), 4.16 (t, 2H), 2.53 (m,1H), 4.65 (s, 2H), 6.71 (m, 2H), 7.35 (s, 1H)

[1296] LRMS: m/z (ES⁺) 437 [MH⁺]

[1297] Also isolated was the title compound of Example 130 (16 mg):

[1298]¹H-NMR (CDCl₃, 400 MHz) δ: 1.25 (d, 6H), 1.80 (m, 4H), 2.63 (m,4H), 2.90 (m, 2H), 3.02 (m, 2H), 3.86 (s, 3H), 4.02 (m, 2H), 4.25 (m,2H), 4.59 (m, 1H), 4.75 (s, 2H), 6.68 (s, 1H), 6.71 (s, 1H), 7.29 (s,1H)

[1299] LRMS: m/z (ES⁻) 435 [M-H⁻]

EXAMPLE 1315-Chloro-7-methoxy-2-(5-pyrrolidin-1-ylmethyl-3,4-dihydro-1H-[2,6]naphthyridin-2-yl)-3H-quinazolin-4-onedihydrochloride

[1300]

[1301] The title compound was obtained from the chloro compound frompreparation 273 and the amine from preparation 113 in 74% yieldfollowing the procedure described in

EXAMPLE 86.

[1302]¹H-nmr (DMSOd₆ 400 MHz) δ: 1.63 (m, 4H), 2.41 (m, 4H), 3.00 (t,2H), 4.69 (s, 2H), 3.80 (s, 3H), 3.88 (t, 2H), 4.81 (s, 2H), 6.68 (d,1H), 6.71 (d, 1H), 7.12 (d, 1H), 8.24 (d, 1H), 11.20 (s, 1H)

[1303] LRMS: m/z (ES⁺) 426 [MH⁺]

[1304] Microanalysis: Found: C, 49.42; H, 5.63; N, 12.51; C₂₂H₂₄CIN₅O₂2HCl 2H₂O requires; C, 49.40; H, 5.65; N, 13.09%

EXAMPLE 1325-Isopropyl-7-methoxy-2-[2-(4-methyl-piperazin-1-yl)-7,8-dihydro-5H-[1,6]naphthyridin-6-yl]-3H-quinazolin-4-onetrihydrochloride

[1305]

[1306] The chloro compound from preparation 269 (101 mg, 0.4 mmol) wasadded to the amine from preparation 110 (104 mg, 0.45 mmol) in n-butanol(5 ml) containing N,N-diisopropylethylamine (129 μl, 1 mmol) and themixture was heated under reflux for 2 hours. The reaction mixture wascooled to room temperature and the solid formed was isolated byfiltration. The material obtained was dissolved in 5% methanol indichloromethane and ethereal hydrogen chloride (1M, 2 ml) was added. Thesolvent was evaporated under reduced pressure and the residue was driedunder vacuum to give the title compound (176 mg).

[1307]¹H-nmr (DMSOd₆ 400 MHz) δ: 1.19 (d, 6H), 2.77 (s, 3H), 3.00 (m,4H), 3.34 (t, 2H), 3.47 (m, 2H), 3.83 (s, 3H), 4.40 (m, 3H), 4.91 (s,2H), 6.81 (s, 1H), 6.90 (d, 1H), 7.50 (m, 2H), 13.38 (s, 1H)

[1308] LRMS: m/z (ES⁺) 449 [MH⁺]

[1309] Microanalysis: Found: C, 53.26; H, 6.49; N, 14.90; C₂₅H₃₂N₆O 3HCl0.25H₂O requires; C, 53.39; H, 6.36; N, 14.94%

EXAMPLE 1335-Isopropyl-7-methoxy-2-(5-methylaminomethyl-3,4-dihydro-1H-[2,6]naphthyridin-2-yl)-3H-quinazolin-4-onedihydrochloride

[1310]

[1311] The protected amine from preparation 297 (59 mg, 0.12 mmol) wasdissolved in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) wasadded. The reaction mixture was stirred at room temperature for 30minutes and then the solvent was evaporated under reduced pressure. Theresidue was purified by chromatography on silica gel using ammoniumhydroxide and methanol in dichloromethane as eluant (1:7:93). Thematerial obtained was dissolved in dichloromethane and ethereal hydrogenchloride (1M, 1 ml) was added. The solvent was evaporated under reducedpressure and the residue was dried under vacuum to give the titlecompound as an off white solid (26 mg).

[1312]¹H-nmr (DMSOd₆ 400 MHz) δ: 1.19 (d, 6H), 2.63 (s, 3H), 2.98 (t,2H), 3.84 (s, 3H), 4.15 (t, 2H), 4.30 (s, 2H), 4.41 (m, 1H), 5.12 (s,2H), 6.80 (s, 1H), 7.26 (d, 1H), 7.55 (s, 1H), 8.46 (d, 1H), 9.26 (s,1H)

[1313] LRMS: m/z (ES⁺) 394 [MH⁺]

[1314] All of the compounds illustrated in examples 1 to 133 display pA2values versus α1L (in the method described above) of greater than 7.

[1315] Particular compounds of interest display the following pA2 valuesversus α1L (in the method described above): Example Number pA2 v α1L 79.5 8 9.6 10 9.7 11 10.0 12 9.7 16 9.5 20 9.8 21 10 38 9.5 39 9.6

1. A compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹represents C₁₋₄ alkyl; R² represents halo, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₃₋₆ cycloalkyloxy, —SO₂(C₁₋₄ alkyl), C₁₋₄ alkyloxy (optionallysubstituted by C₃-C₆ cycloalkyl or C₁-C₄ alkoxy), Het or —OHet; R³represents a bicyclic group of the formula

 wherein X and Y are selected from C and N, provided that at least oneis C; Ring A together with X and Y represents a 5- or 6-memberedaromatic ring containing 0, 1, 2 or 3 nitrogen atoms in the ring; n is0, 1 or 2 L independently represents a direct link, C₁₋₄ alkylene orC₁₋₄ alkoxyalkylene; R⁴ independently represents H, —NR⁵R⁶, C₃₋₆cycloalkyl, —OR⁷, Het¹ or Het⁴; R⁵ and R⁶ are independently selectedfrom H, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, —SO₂(C₁₋₄ alkyl)and C₁₋₄ alkyl (optionally substituted with —OR⁸, —NR¹⁰R¹¹, Het¹ orHet⁴); R⁷ is selected from H, C₁₋₄ alkyl, C₁₋₄ alkoxyalkyl, C₃₋₆cycloalkyl, Het² and C₁₋₄ alkyl-Het³; R⁸ is H or C₁₋₄ alkyl; Het, Het¹,Het² and Het³ independently represent a 4 to 7 membered saturatedheterocyclic group which may be mono- or bi-cyclic and which containsone or more heteroatoms selected from N, O or S, optionally substitutedwith OR⁹ and/or C₁₋₄ alkyl optionally substituted by OR⁹; Het⁴represents a 5 or 6 membered unsaturated heterocyclic group containingone or more heteroatoms selected from N, O or S, optionally substitutedwith C₁₋₄ alkyl; R⁹ is H or C₁₋₄ alkyl; R¹⁰ and R¹¹ are independentlyselected from H and C₁₋₄ alkyl.
 2. A compound of formula (I) accordingto claim 1, or a pharmaceutically acceptable salt or solvate thereof,wherein Het, Het¹, Het² and Het³ contain at least one N atom and arelinked to L through an N atom.
 3. A compound of formula (I) according toclaim 1 or claim 2, or a pharmaceutically acceptable salt or solvatethereof, wherein Het, Het¹, Het² and Het³ include azetidine,pyrrolidine, piperidine, piperazine, azepane, morpholine,homomorpholine, or one of the following ring systems

optionally substituted by OR⁹, C₁₋₄ alkyl optionally substituted by OR⁹.4. A compound of formula (I) according to any of the preceding claims,or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ isCH₃.
 5. A compound of formula (I) according to any of the precedingclaims, or a pharmaceutically acceptable salt or solvate thereof,wherein R² is cyclopropyl.
 6. A compound of formula (I) according to anyof the preceding claims, or a pharmaceutically acceptable salt orsolvate thereof, wherein L represents methylene.
 7. A compound offormula (I) according to any of the preceding claims, or apharmaceutically acceptable salt or solvate thereof, wherein R³represents a group chosen from a or b (bonded to the quinazolinonethrough the N-atom as indicated)

where LR⁴ is CH₂Het¹ or CH₂NR⁵R⁶ and Het¹, R⁵ and R⁶ are as defined inclaim
 1. 8. A compound of formula (I) according to claim 7, wherein Het¹is N-linked morpholinyl
 9. A compound of formula (I) according to any ofthe preceding claims, or a pharmaceutically acceptable salt or solvatethereof, wherein R⁵ and R⁶ are independently selected from H or C₁₋₃alkyl optionally substituted by OCH₃.
 10. A compound of formula (I)according to any of the preceding claims, or a pharmaceuticallyacceptable salt or solvate thereof, wherein Het, Het¹, Het² and Het³ areselected from the group comprising pyrrolidine, piperidine, morpholineand


11. A compound of formula (I) as defined in claim 1 selected from:5-cyclopropyl-7-methoxy-2-(2-([dimethylamino]methyl)-7,8-dihydro[1,6]naphthyridin-6(5H)-yl)-4(3H)-quinazolinone,i.e. example 7;5-cyclopropyl-7-methoxy-2-(2-(1-pyrrolidinylmethyl)-7,8-dihydro[1,6]naphthyridin-6(5H)-yl)-4(3H)-quinazolinone,i.e. example 8;5-cyclopropyl-7-methoxy-2-(2-(4-methoxypiperidin-1-ylmethyl)-7,8-dihydro[1,6]naphthyridin-6(5H)-yl)-4(3H)-quinazolinone,i.e. example 10;5-cyclopropyl-7-methoxy-2-(2-(4-morpholinylmethyl)-7,8-dihydro[1,6]naphthyridin-6(5H)-yl)-4(3H)-quinazolinone,i.e. example 11;5-cyclopropyl-7-methoxy-2-(2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-7,8-dihydro[1,6]naphthyridin-6(5H)-yl)-4(3H)-quinazolinone,i.e. example 12;5-cyclopropyl-7-methoxy-2-(5-([dimethylamino]methyl)-3,4-dihydro[2,6]naphthyridin-2(1H)-yl)-4(3H)-quinazolinone,i.e. example 16;5-cyclopropyl-7-methoxy-2-(5-(4-morpholinylmethyl)-3,4-dihydro[2,6]naphthyridin-2(1H)-yl)-4(3H)-quinazolinone,i.e. example 20;5-cyclopropyl-7-methoxy-2-(5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-3,4-dihydro[2,6]naphthyridin-2(1H)-yl)-4(3H)-quinazolinone,i.e. example 21;5-cyclopropyl-7-methoxy-2-(5-(1-pyrrolidinylmethyl)-3,4-dihydro[2,6]naphthyridin-2(1H)-yl)-4(3H)-quinazolinone,i.e. example 38;5-cyclopropyl-7-methoxy-2-(5-(1-piperidinylmethyl)-3,4-dihydro[2,6]naphthyridin-2(1H)-yl)-4(3H)-quinazolinone,i.e. example 39; and pharmaceutically acceptable salts or solvatesthereof. 12.5-cyclopropyl-7-methoxy-2-(2-(4-morpholinylmethyl)-7,8-dihydro[1,6]naphthryidin-6(5H)-yl)-4(3H)-quinazolinone,or a pharmaceutically acceptable salt or solvate thereof.
 13. Apharmaceutical composition including a compound of the formula (I) asdefined in any of claims 1 to 12, or a pharmaceutically acceptable saltor solvate thereof, together with a pharmaceutically acceptableexcipient, diluent or carrier.
 14. A compound of the formula (I) asdefined in any of claims 1 to 12, or a pharmaceutically acceptable saltor solvate thereof, for use as a medicament.
 15. The use of a compoundof the formula (I) as defined in any of claims 1 to 12, or of apharmaceutically acceptable salt or solvate, in the manufacture of amedicament for the treatment of hypertension, myocardial infarction,male erectile dysfunction, hyperlipidaemia, cardiac arrhythmia, glaucomaand benign prostatic hyperplasia.
 16. The use according to claim 15,wherein the treatment is of benign prostatic hyperplasia.
 17. A methodof treating hypertension, myocardial infarction, male erectiledysfunction, hyperlipidaemia, cardiac arrhythmia and benign prostatichyperplasia in a mammal, which comprises administering a therapeuticallyeffective amount of a compound of the formula (I) as defined in any ofclaims 1 to 12, or with a pharmaceutically acceptable salt, solvate orcomposition thereof, to a mammal in need of such treatment.
 18. A methodaccording to claim 17, for treating benign prostatic hyperplasia.
 19. Aprocess for the preparation of a compound of formula (I) as defined inclaim 1, or a pharmaceutically acceptable salt or solvate thereof,comprising reacting a quinazolinone (II) with an amine (III):

wherein R¹, R², X, Y, LR⁴ and n are as defined in claim 1 and LGrepresents a leaving group, and where desired or necessary convertingthe resulting compound of formula (I) into a pharmaceutically acceptablesalt or solvate.
 20. A compound of formula (II), as defined in claim 19.